Riluzole prodrugs and their use

ABSTRACT

Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/127,684 filed Mar. 3, 2015, which is herein incorporated by referencein its entirety.

STATEMENT OF FEDERALLY FUNDED RESEARCH

The U.S. Government has a paid-up license in this invention and theright in limited circumstances to require the patent owner to licenseothers on reasonable terms as provided for by the terms of grant numberR43 CA156781-01 and R44 CA156781-02 awarded by the National CancerInstitute.

FIELD OF INVENTION

The present invention describes compounds and methods useful as prodrugagents, useful for the treatment of cancers including melanoma throughthe release of riluzole.

BACKGROUND OF THE INVENTION

A recently conducted Phase 0 human clinical trial of riluzole (Rilutek™)demonstrated dramatic efficacy in certain melanoma patients after only14 days of treatment. Riluzole, the only FDA approved drug to treatamyotrophic lateral sclerosis (ALS), showed clinical or radiologicevidence of tumor response in four of 12 patients with Stage III and IVmelanoma, cancer with a poor prognosis and severely limited treatmentoptions.

The use of riluzole (RILUTEK®) for cancers or other diseases issignificantly constrained due to high levels of variability in hepaticmetabolism of the drug, dose dependent effects on the liver, and anegative food effect associated with the drug when administered withmeals. The approved USPI notes that that riluzole tablets should betaken at least 1 hour before, or 2 hours after, a meal to avoidfood-related decreases in bioavailability that may interfere with theability to achieve or maintain therapeutic blood concentrations. Suchfasting requirements amount to six hours of fasting per day whenadministered twice daily. Despite riluzole's approval over 20 years ago,these multiple clinical constraints of riluzole have persisted andlimited the clinical application of riluzole to other disease states. Wedescribe here prodrugs of riluzole in order to improve the clinicalefficacy of riluzole-based therapy, increase patient compliance, andrelieve human suffering. Metastatic melanoma has few treatment options,and the current therapeutic standard of care is dacarbazine which is ahighly cytotoxic drug with severe side effects including vomiting,headache and hair loss. Treatment with dacarbazine has a medianprogression-free enhancement of survival time of only 1.5 months.Riluzole (Rilutek™) is a generally non-toxic drug and currently the onlyFDA-approved treatment for amyotrophic lateral sclerosis (ALS or LouGehrig's disease).

We have recently shown that riluzole has dramatic anti-melanoma activityin vitro cellular assays, in mice and in a Phase 0 human clinical trial.In the clinic, four of twelve melanoma patients showed significantclinical or radiologic evidence of Stage III and IV tumor response.These results, along with the mild side-effect profile that riluzole hasshown among ALS patients, suggests that this drug has significantpotential for use as an improved treatment for metastatic melanoma.However, the therapeutic utility of riluzole itself in ALS andeventually for melanoma is very constrained by rapid first-passmetabolism in the liver and an exceptionally high level ofpatient-to-patient variability in the extent of the Cyp1A2-mediatedoxidative metabolism that is observed.

Riluzole is also believed to be clinically relevant in additionaldisease states, including a variety of central nervous system (“CNS”)and depression/anxiety states. These include, but are not limited to,bipolar disorder, treatment resistant and major depression,obsessive-compulsive disorder, general anxiety disorder, panic disorder,social anxiety, mood disorders, cognitive disorders, dementia,agitation, apathy, psychoses, post-traumatic stress disorders,irritability, disinhibition, learning disorders, memory loss,personality disorders, bipolar disorders, Rett syndrome, eatingdisorders, conduct disorder, neurodegenerative disorders, paindisorders, supranuclear palsy, frontotemporal dementia, frontotemporallobar degeneration, delirium, Alzheimer's disease, mild cognitiveimpairment, mild cognitive impairment due to Alzheimer's disease, drugaddiction, tinnitus, mental retardation, spinal muscular atrophy,radiation therapy, multiple sclerosis, chronic cerebellar ataxia,hereditary spinocerebellar ataxia, spinocerebellar ataxia, sporadicataxia, episodic ataxia, Friedreich Ataxia, Multisystem Atrophy, ataxiaassociated with Anti-GAD antibodies target and onconeural antigen,essential tremor, cervical spondylotic myelopathy, spinal cord injury,hereditary cerebellar ataxia, Tourette syndrome, autism spectrumdisorder, schizophrenia, fragile X syndrome, Parkinson's Disease,Progressive Supranuclear Palsy, Dementia with Lewy Bodies, andHuntington's disease. However, riluzole can have issues in livermetabolism. Pro-drugs of riluzole will provide more predictablepharmacokinetic properties and metabolic profiles for the parentcompound, leading to an improved therapeutic effect in each of theaforementioned disease states. Riluzole has been approved for 25 yearswithout solutions to the pharmacokinetic and metabolic limitations ofthe drug. The intrinsic property of the drug itself teaches away fromthe sublingual administration of riluzole. Riluzole has a very lowsolubility in water, poor oral palatability, pH dependent chemicalstability, and intense as well as persistent numbness or burningsensation throughout the oral cavity. Techniques aimed at reducing theseundesirable effects, such as use of chelating agents, would onlyfacilitate the oral swallowing and gastric absorption rather thanresulting in sublingual absorption.

It has also been demonstrated that riluzole is clinically relevant togeneralized anxiety disorder (GAD) and is useful for the attenuation ofpresynaptic glutamate release. Riluzole is also useful for thenormalization, enhancement or potentiation of the uptake of glutamate byglia (Coric et al. U.S. Pat. No. 8,778,979).

There is a long felt need for new treatments for melanoma that are bothdisease-modifying and effective in treating patients that are refractoryto current treatments. The present invention addresses the need toidentify new treatments for melanoma by identifying novel prodrugs ofriluzole which possess enhanced stability to hepatic metabolism and aredelivered into systemic circulation by oral administration. The presentinvention can also treat or prevent various neurological or CNS statesas well as depression/anxiety states. The riluzole prodrugs are cleavedto release riluzole in the plasma via either an enzymatic or generalbiophysical release process.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed toward riluzole derivatives of formula(I),

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof, wherein:R¹ is selected from the group consisting of C₁-C₆ fluoroalkyl, OR²,(CR⁶R^(6b))_(m)NHR⁷, CR^(10a)R^(10b)NR¹¹R¹².

R² is selected from the group consisting of CH₂(CH₂)_(n)NR^(3a)R^(3b),

R^(3a) and R^(3b) are independently selected from the group consistingof hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, and CO₂R⁴;R^(3a) and R^(3b) cannot both be C₁-C₆ alkyl;R^(3a) and R^(3b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedheterocyclic ring consisting of two to five carbon atoms and a memberselected from the group consisting of O, NR, S, and SO₂;n is 1 or 2;R⁴ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branchedalkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl. C₂-C₆ alkynyl, optionallysubstituted phenyl, and optionally substituted benzyl;R⁵ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branchedalkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R^(6a) and R^(6b) are at each occurrence independently selected from thegroup consisting of hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₇ branched alkyl, optionally substitutedC₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R^(6a) and R^(6b) are taken together with the atom to which they arebound to form an optionally substituted 6 membered ring;m is 1, 2, or 3;R⁷ is selected from the group consisting of COCR^(8a)R^(8b)(NHR⁹),

R^(8a) and R^(8b) are at each occurrence independently selected from thegroup consisting of hydrogen, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂OH, CH(OH)CH₃, CH₂Ph, CH₂(4-OH—Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH,CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, andCH₂CH₂CONH₂;R⁹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;Y is at each occurrence independently selected from the group consistingof H₂ or O;R^(10a) and R^(10b) are at each occurrence independently selected fromthe group consisting of hydrogen, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH, CH₂OH, CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂(CCH),CH₂(cyclohexyl), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂;R^(10a) and R^(10b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedcarbocyclic ring;R¹¹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇,cycloalkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, and C₂-C₆ alkynyl;R^(10a) and R¹¹ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom, and R¹² is not hydrogen;R^(10b) and R¹¹ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom, and R¹² is not hydrogen;R¹² is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, COCR^(13a)R^(13b)NR^(15a)R^(15b),COCR^(13a)R^(13b)OR¹⁴, SO₂CR^(13a)R^(13b)NR^(15a)R^(15b),COCR^(13A)R^(13b)NHSO₂R^(15a)

and (CR^(19a)R^(19b))_(q)NHR²⁰, and when R¹² is hydrogen, R¹¹ cannot behydrogen;R¹¹ and R¹² are taken together with the atom to which they are bound toform an optionally substituted four to six membered saturatedheterocyclic ring containing a nitrogen atom and optionally containingan additional heteroatom from the group consisting of N and O;R^(13a) and R^(13b) are at each occurrence independently selected fromthe group consisting hydrogen, CH₃, CH₂CH₃, CH₂CH₂CH₃. CH₂CCH, CH(CH₃)₂,CH₂CH(CH₁)₂, CH(CH₃)CH₂CH₃. CH₂OH, CH₂OCH₂Ph, CH₂CH₂OCH₂Ph, CH(OH)CH₃,CH₂Ph, CH₂(cyclohexyl). CH₂(4-OH-Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH,CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, andCH₂CH₂CONH₂;R^(13a) and R^(13b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedcarbocyclic ring;R^(13a) and R^(13b) are taken together with the atom to which they arebound to form an optionally substituted six membered saturatedheterocyclic ring with one O atom within the ring;R^(13a) and R¹⁴ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom;R^(13a) and R^(13b) are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom;Y¹ is at each occurrence independently selected from the groupconsisting of H₂, O, and —H/—OCH₂Ph;R¹⁴ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl. C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R^(15a) and R^(15b) are at each occurrence independently selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl. C₂-C₆ alkenyl. C₂-C₆ alkynyl C₁-C₆ fluoroalkyl.COR²¹. CH₂R²¹, SO₂R²², an optionally substituted four to six memberedsaturated heterocyclic ring containing a heteroatom selected from thegroup consisting of NR²⁴ and O, COCHR²³NH₂,

R^(15a) and R^(15b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedheterocyclic ring consisting of two to five carbon atoms and a memberselected from the group consisting of O, NR⁵, S, and SO₂;R¹⁶ is at each occurrence independently selected from the groupconsisting of CH₂, O. C═O. and NH;R¹⁷ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R¹⁸ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R¹⁷ and R¹⁸ are taken together with the atoms to which they are bound toform an optionally substituted five or six membered ring containing twonitrogen atoms;R^(19a) and R^(19b) are at each occurrence independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₇ branched alkyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted C₂-C₆ alkenyl, and optionallysubstituted C₂-C₆ alkynyl;R^(19a) and R^(19b) are taken together with the atom to which they arebound to form an optionally substituted 3 to 6 membered carbocyclicring;R²⁰ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl. C₂-C₆ alkenyl, and C₂-C₆ alkynyl;q is 1, or 2;R²¹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ fluoroalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl;R²² is at each occurrence independently selected from the groupconsisting of C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl;R²³ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃.CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph,CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H,CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂;R²⁴ is at each occurrence independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, COR²⁵, and SO₂—C₁₋₆alkyl;R²⁵ is at each occurrence independently selected from the groupconsisting of H, C₁-C₆ alkyl. C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl.C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, C₁-C₆alkoxy, and C₁-C₆ alkylamino.

The compounds of the present invention include compounds having formula(II):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(III):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(IV):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(V):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VI):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VII):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VIII):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(IX):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(X):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XI):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XII):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XIII):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XIV):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XV):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVI):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVII):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVIII)

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof, wherein:R²³ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃.CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph,CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H,CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂.

The present invention further relates to compositions comprising:

an effective amount of one or more compounds according to the presentinvention and an excipient.

The present invention yet further relates to an effective amount of oneor more compounds according to the present invention and an anticanceragent.

The present invention also relates to a method for treating orpreventing cancer, particularly melanoma, said method comprisingadministering to a subject an effective amount of a compound orcomposition according to the present invention, possibly in conjunctionwith an excipient and/or an anticancer agent.

The present invention also relates to a method for treating orpreventing disease or conditions associated with cancer, particularlymelanoma. Said methods comprise administering to a subject an effectiveamount of a compound or composition according to the present invention,possibly in conjunction with an excipient and/or an anticancer agent.

Cancers that may be treated or prevented by administering to a subjectan effective amount of a compound or composition according to thepresent invention, or a pharmaceutically acceptable salt, solvate,anomer, enantiomer or hydrate thereof, possibly with an excipient or ananticancer agent, includi ovarian cancer, cervical cancer, breastcancer, prostate cancer, testicular cancer, lung cancer, renal cancer,colorectal cancer, skin cancer, brain cancer including glioma andglioblastoma, and leukemia. The present invention also provides asublingual or sustained release formulation which may comprise aneffective amount of riluzole or a pharmaceutically acceptable salts,solvate, anomers, enantiomers, hydrate or prodrugs thereof to treatcancers in combination with immunotherapies (including alone or incombination with vaccines, anti-PD1, anti-PDL1, anti-CTLA4 or otherimmunotherapy or checkpoint inhibitor targets including: CTLA4,cytotoxic T-lymphocyte-associated antigen 4; Ig, immunoglobulin; LAG3,lymphocyte activation gene 3; mAbs, monoclonal antibodies; PD1,programmed cell death protein 1; PDL, PD1 ligand; TLM3, T cell membraneprotein 3, CD40L, A2aR, adenosine A2a receptor; B7RP1, B7-relatedprotein 1; BTLA, B and T lymphocyte attenuator; GAL9, galectin 9; HVEM,herpesvirus entry mediator; ICOS, inducible T cell co-stimulator; IL,interleukin; KIR, killer cell immunoglobulin-like receptor; LAG3,lymphocyte activation gene 3; PD1, programmed cell death protein 1; PDL,PD1 ligand; TGFβ, transforming growth factor-β; TIM3, T cell membraneprotein 3; CD27).

The present invention also relates to a method for treating orpreventing various neurological or CNS states as well asdepression/anxiety states in which riluzole is clinically relevantincluding, but are not limited to, bipolar disorder, treatment resistantand major depression, general anxiety disorder, panic disorder, socialanxiety, mood disorders, cognitive disorders, dementia, agitation,apathy, psychoses, post-traumatic stress disorders, irritability,disinhibition, learning disorders, memory loss, personality disorders,bipolar disorders, Rett syndrome, eating disorders, conduct disorder,neurodegenerative disorders, pain disorders, supranuclear palsy,frontotemporal dementia, frontotemporal lobar degeneration, delirium,Alzheimer's disease, mild cognitive impairment, mild cognitiveimpairment due to Alzheimer's disease, drug addiction, tinnitus, mentalretardation, obsessive-compulsive disorder, spinal muscular atrophy,radiation therapy, multiple sclerosis, chronic cerebellar ataxia,hereditary spinocerebellar ataxia, spinocerebellar ataxia, sporadicataxia, episodic ataxia, Friedreich Ataxia, Multisystem Atrophy, ataxiaassociated with Anti-GAD antibodies target and onconeural antigen,essential tremor, cervical spondylotic myclopathy, spinal cord injury,hereditary cerebellar ataxia, Tourette syndrome, autism spectrumdisorder, schizophrenia, fragile X syndrome, Parkinson's Disease,Progressive Supranuclear Palsy, Dementia with Lewy Bodies, andHuntington's disease, said method comprising administering to a subjectan effective amount of a compound or composition according to thepresent invention, possibly with an excipient or other CNS drug such asserotonin reuptake inhibitor (SRI).

The present invention yet further relates to a method of enhancing theactivity of a serotonin reuptake inhibitor (SRI) in an individual inneed thereof. The methods comprise co-administering to the individual aneffective amount of a compound or composition according to the presentinvention and a SRI.

In certain embodiments, the serotonin reuptake inhibitor can becitalopram, escitalopram, flouxetine, fluvoxamine, paroxetine,sertraline, trazodone, venlafaxine, mirtazepine, clomipramine, orcombinations with other psychotropic medications including ananti-psychotic, an anticonvulsant, a tricyclic antidepressant, amonoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, aselective serotonin-norepinephrine reuptake inhibitor, a norepinephrinedopamine reuptake inhibitor, a serotonin-2 antagonist reuptakeinhibitor, a benzodiazepine, a wakefulness promoting agent, anti-manicagent, or a combination of one or more of the foregoing. The presentinvention further relates to a process for preparing the riluzoleprodrugs of the present invention.

These and other objects, features, and advantages will become apparentto those of ordinary skill in the art from a reading of the followingdetailed description and the appended claims. All percentages, ratiosand proportions herein are by weight, unless otherwise specified. Alltemperatures are in degrees Celsius (° C.) unless otherwise specified.All documents cited are in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Time concentration curve for example 125 and released riluzolevia both intravenous and oral administration.

FIG. 2: Melanoma (C8161) xenograft study in nude mice with example 125and riluzole given orally (RIL=Riluzole).

FIG. 3: Time-concentration curves for2-Amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamide (Example 204)and released riluzole via both intravenous and oral administration.

FIG. 4: Melanoma (C8161) xenograft study in nude mice with example 204and riluzole given orally (RIL=Riluzole).

FIG. 5: PK in fasted male mice for Example 204, IV administration, 1mg/kg, and PO administration 5 mg/kg. Monitor disappearance of Prodrugand appearance of riluzole.

FIG. 6: PK in Cynomolgus Monkey for Example 204, IV administration, 1mg/kg, and PO administration 5 mg/kg. Monitor appearance of riluzole.

DETAILED DESCRIPTION OF THE INVENTION

The prodrugs of the present invention are capable of treating andpreventing cancers such as melanoma by releasing riluzole in vivo.Prodrugs of riluzole have enhanced stability to hepatic metabolism andare delivered into systemic circulation by oral administration, and arethen cleaved to release riluzole in the plasma via either an enzymaticor general biophysical release process. Riluzole has dramaticanti-melanoma activity in vitro, in mice and in a Phase 0 human clinicaltrial. The pro-drugs of the present invention are also capable oftreating and preventing other disease states in which riluzole isclinically relevant including, but are not limited to, amyotrophiclateral sclerosis (ALS) bipolar disorder, treatment resistant and majordepression, general anxiety disorder, panic disorder, social anxiety,mood disorders, cognitive disorders, dementia, agitation, apathy,psychoses, post-traumatic stress disorders, irritability, disinhibition,learning disorders, memory loss, personality disorders, bipolardisorders, Rett syndrome, eating disorders, conduct disorder,neurodegenerative disorders, pain disorders, supranuclear palsy,frontotemporal dementia, frontotemporal lobar degeneration, delirium,Alzheimer's disease, mild cognitive impairment, mild cognitiveimpairment due to Alzheimer's disease, drug addiction, tinnitus, mentalretardation, obsessive-compulsive disorder, spinal muscular atrophy,radiation therapy, multiple sclerosis, chronic cerebellar ataxia,hereditary spinocerebellar ataxia, spinocerebellar ataxia, sporadicataxia, episodic ataxia, Friedreich Ataxia, Multisystem Atrophy, ataxiaassociated with Anti-GAD antibodies target and onconeural antigen,essential tremor, cervical spondylotic myelopathy, spinal cord injury,hereditary cerebellar ataxia, Tourette syndrome, autism spectrumdisorder, schizophrenia, fragile X syndrome, Parkinson's Disease,Progressive Supranuclear Palsy, Dementia with Lewy Bodies, andHuntington's disease.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present teachings also consistessentially of, or consist of, the recited components, and that theprocesses of the present teachings also consist essentially of, orconsist of, the recited processing steps.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components and can be selected from the groupconsisting of two or more of the recited elements or components.

The use of the singular herein includes the plural (and vice versa)unless specifically stated otherwise. In addition, where the use of theterm “about” is before a quantitative value, the present teachings alsoinclude the specific quantitative value itself, unless specificallystated otherwise.

It should be understood that the order of steps or order for performingcertain actions is immaterial so long as the present teachings remainoperable. Moreover, two or more steps or actions can be conductedsimultaneously

As used herein, the term “halogen” shall mean chlorine, bromine,fluorine and iodine.

As used herein, unless otherwise noted, “alkyl” and “aliphatic” whetherused alone or as part of a substituent group refers to straight andbranched carbon chains having 1 to 20 carbon atoms or any number withinthis range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms.Designated numbers of carbon atoms (e.g. C₁-C₆) shall referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger alkyl-containing substituent. Non-limitingexamples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Alkyl groupscan be optionally substituted. Non-limiting examples of substitutedalkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl,aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl,3-carboxypropyl, and the like. In substituent groups with multiple alkylgroups such as (C₁-C₆ alkyl)₂amino, the alkyl groups may be the same ordifferent.

As used herein, “cycloalkyl.” whether used alone or as part of anothergroup, refers to a non-aromatic carbon-containing ring includingcyclized alkyl, alkenyl, and alkynyl groups. e.g., having from 3 to 14ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms,or even 3 to 4 ring carbon atoms, and optionally containing one or more(e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can bemonocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused,bridged, and/or spiro ring systems), wherein the carbon atoms arelocated inside or outside of the ring system. Any suitable ring positionof the cycloalkyl group can be covalently linked to the defined chemicalstructure. Cycloalkyl rings can be optionally substituted. Nonlimitingexamples of cycloalkyl groups include: cyclopropyl,2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl,2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl,decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl,4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl,octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl,decahydroazulenyl: bicyclo[6.2.0]decanyl, decahydronaphthalenyl, anddodecahydro-1H-fluorenyl. The term “cycloalkyl” also includescarbocyclic rings which are bicyclic hydrocarbon rings, non-limitingexamples of which include, bicyclo-[2.1.1]hexanyl,bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl,1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, andbicyclo[3.3.3]undecanyl.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Haloalkyl groupsinclude perhaloalkyl groups, wherein all hydrogens of an alkyl grouphave been replaced with halogens (e.g., —CF₃, CF₂CF₃). Haloalkyl groupscan optionally be substituted with one or more substituents in additionto halogen. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl groups.

The term “alkoxy” refers to the group —O-alkyl, wherein the alkyl groupis as defined above. Alkoxy groups optionally may be substituted. Theterm v cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms andat least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran).C₃-C₆ cyclic alkoxy groups optionally may be substituted.

The term “aryl,” wherein used alone or as part of another group, isdefined herein as an unsaturated, aromatic monocyclic ring of 6 carbonmembers or to an unsaturated, aromatic polycyclic ring of from 10 to 14carbon members. Aryl rings can be, for example, phenyl or naphthyl ringeach optionally substituted with one or more moieties capable ofreplacing one or more hydrogen atoms. Non-limiting examples of arylgroups include: phenyl, naphthylen-1-yl, naphthylen-2-yl,4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl,2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl,3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl,and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example,phenyl or naphthyl rings fused with one or more saturated or partiallysaturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl,indanyl), which can be substituted at one or more carbon atoms of thearomatic and/or saturated or partially saturated rings.

The term “arylalkyl” or “aralkyl” refers to the group -alkyl-aryl, wherethe alkyl and aryl groups are as defined herein. Aralkyl groups of thepresent invention are optionally substituted.

Examples of arylalkyl groups include, for example, benzyl,1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl,fluorenylmethyl and the like.

The terms “heterocyclic” and/or “heterocycle” and/or “heterocylyl.”whether used alone or as part of another group, are defined herein asone or more ring having from 3 to 20 atoms wherein at least one atom inat least one ring is a heteroatom selected from nitrogen (N), oxygen(O), or sulfur (S), and wherein further the ring that includes theheteroatom is non-aromatic. In heterocycle groups that include 2 or morefused rings, the non-heteroatom bearing ring may be aryl (e.g.,indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclegroups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Oneor more N or S atoms in a heterocycle group can be oxidized. Heterocyclegroups can be optionally substituted.

Non-limiting examples of heterocyclic units having a single ringinclude: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl,isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl,hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl,piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl(valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole,and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclicunits having 2 or more rings include: hexahydro-1H-pyrrolizinyl,3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl,3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,chromanyl, isochromanyl, indolinyl, isoindolinyl, anddecahydro-1H-cycloocta[b]pyrrolyl.

The term “heteroaryl.” whether used alone or as part of another group,is defined herein as one or more rings having from 5 to 20 atoms whereinat least one atom in at least one ring is a heteroatom chosen fromnitrogen (N), oxygen (O), or sulfur (S), and wherein further at leastone of the rings that includes a heteroatom is aromatic. In heteroarylgroups that include 2 or more fused rings, the non-heteroatom bearingring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) oraryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplaryheteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5ring heteroatoms independently selected from nitrogen (N), oxygen (O),or sulfur (S). One or more N or S atoms in a heteroaryl group can beoxidized. Heteroaryl groups can be substituted. Non-limiting examples ofheteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl,oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl,pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limitingexamples of heteroaryl rings containing 2 or more fused rings include:benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl,9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl,7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,benzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl,quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl,8-hydroxy-quinolinyl, and isoquinolinyl.

Unless otherwise noted, when two substituents are taken together to forma ring having a specified number of ring atoms (e.g., R² and R³ takentogether with the nitrogen (N) to which they are attached to form a ringhaving from 3 to 7 ring members), the ring can have carbon atoms andoptionally one or more (e.g., 1 to 3) additional heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Thering can be saturated or partially saturated and can be optionallysubstituted.

For the purposed of the present invention fused ring units, as well asspirocyclic rings, bicyclic rings and the like, which comprise a singleheteroatom will be considered to belong to the cyclic familycorresponding to the heteroatom containing ring. For example,1,2,3,4-tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclicunit, 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit. When a fused ring unit contains heteroatoms in both a saturatedand an aryl ring, the aryl ring will predominate and determine the typeof category to which the ring is assigned. For example,1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit.

Whenever a term or either of their prefix roots appear in a name of asubstituent the name is to be interpreted as including those limitationsprovided herein. For example, whenever the term “alkyl” or “aryl” oreither of their prefix roots appear in a name of a substituent (e.g.,arylalkyl, alkylamino) the name is to be interpreted as including thoselimitations given above for “alkyl” and “aryl.”

The term “substituted” is used throughout the specification. The term“substituted” is defined herein as a moiety, whether acyclic or cyclic,which has one or more hydrogen atoms replaced by a substituent orseveral (e.g., 1 to 10) substituents as defined herein below. Thesubstituents are capable of replacing one or two hydrogen atoms of asingle moiety at a time. In addition, these substituents can replace twohydrogen atoms on two adjacent carbons to form said substituent, newmoiety or unit. For example, a substituted unit that requires a singlehydrogen atom replacement includes halogen, hydroxyl, and the like. Atwo hydrogen atom replacement includes carbonyl, oximino, and the like.A two hydrogen atom replacement from adjacent carbon atoms includesepoxy, and the like. The term “substituted” is used throughout thepresent specification to indicate that a moiety can have one or more ofthe hydrogen atoms replaced by a substituent. When a moiety is describedas “substituted” any number of the hydrogen atoms may be replaced. Forexample, difluoromethyl is a substituted C₁ alkyl; trifluoromethyl is asubstituted C₁ alkyl; 4-hydroxyphenyl is a substituted aromatic ring;(N,N-dimethyl-5-amino)octanyl is a substituted C₈ alkyl;3-guanidinopropyl is a substituted C₃ alkyl; and 2-carboxypyridinyl is asubstituted heteroaryl.

The variable groups defined herein, e.g., alkyl, cycloalkyl, alkoxy,aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whetherused alone or as part of another group, can be optionally substituted.Optionally substituted groups will be so indicated.

The following are non-limiting examples of substituents which cansubstitute for hydrogen atoms on a moiety: halogen (chlorine (Cl),bromine (Br), fluorine (F) and iodine(I)), —CN, —NO₂, oxo (═O), —OR²⁶,—SR²⁶, —N(R²⁶)₂, —NR²⁶C(O)R²⁶, —SO₂R²⁶, —SO₂R²⁶, —SO₂N(R²⁶)₂, —C(O)R²⁶,—C(O)OR²⁶, —C(O)N(R²⁶)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₁₄ cycloalkyl, aryl, heterocycle, orheteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups isoptionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selectedindependently from halogen, —CN. —NO₂, oxo, and R²⁶; wherein R²⁶, ateach occurrence, independently is hydrogen, —OR²⁷, —SR²⁷, —(O)R²⁷,—C(O)OR²⁷, —C(O)N(R²⁷)₂, —SO₂R²⁷, —S(O)₂OR²⁷, —N(R²⁷)₂, —NR²⁷C(O)R²⁷,C₁₋₆, alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cycloalkyl(e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R²⁶units taken together with the atom(s) to which they are bound form anoptionally substituted carbocycle or heterocycle wherein said carbocycleor heterocycle has 3 to 7 ring atoms; wherein R²⁷, at each occurrence,independently is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, orheteroaryl, or two R²⁷ units taken together with the atom(s) to whichthey are bound form an optionally substituted carbocycle or heterocyclewherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

In some embodiments, the substituents are selected from

-   -   i) OR²⁸; for example, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃;    -   ii) —C(O)R²⁸; for example, —COCH₃, —COCH₂CH₃, —COCH₂CH₂CH₁;    -   iii) —C(O)OR²⁸; for example, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃;    -   iv) —C(O)N(R²⁸)₂; for example, —CONH₂, —CONHCH₃, —CON(CH₃)₂;    -   v) —N(R²⁸)₂; for example, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃);    -   vi) halogen: —F, —Cl, —Br, and —I;    -   vii) —CH_(e)X_(g); wherein X is halogen, m is from 0 to 2,        e+g=3; for example, —CH₂F, —CHF₂, —CF₃, —CC₃, or —CBr₃;    -   viii) —SO₂R²⁸; for example, —SO₂H; —SO₂CH₃; —SO₂C₆H₅;    -   ix) C₁-C₆ linear, branched, or cyclic alkyl;    -   x) Cyano    -   xi) Nitro;    -   xii) N(R²⁸)C(O)R²⁸;    -   xiii) Oxo (═O);    -   xiv) Heterocycle; and    -   xv) Heteroaryl.    -   wherein each R²⁸ is independently hydrogen, optionally        substituted C₁-C₆ linear or branched alkyl (e.g., optionally        substituted C₁-C₄ linear or branched alkyl), or optionally        substituted C₃-C₆ cycloalkyl (e.g optionally substituted C₃-C₄        cycloalkyl); or two R²⁸ units can be taken together to form a        ring comprising 3-7 ring atoms. In certain aspects, each R²⁸ is        independently hydrogen, C₁-C₆ linear or branched alkyl        optionally substituted with halogen or C₃-C₆ cycloalkyl or C₃-C₆        cycloalkyl.

At various places in the present specification, substituents ofcompounds are disclosed in groups or in ranges. It is specificallyintended that the description include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁-C₆ alkyl” is specifically intended to individually discloseC₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅,C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆, alkyl.

For the purposes of the present invention the terms “compound,”“analog,” and “composition of matter” stand equally well for the prodrugagent described herein, including all enantiomeric forms, diastereomericforms, salts, and the like, and the terms “compound,” “analog.” and“composition of matter” are used interchangeably throughout the presentspecification.

Compounds described herein can contain an asymmetric atom (also referredas a chiral center), and some of the compounds can contain one or moreasymmetric atoms or centers, which can thus give rise to optical isomers(enantiomers) and diastereomers. The present teachings and compoundsdisclosed herein include such enantiomers and diastercomers, as well asthe racemic and resolved, enantiomerically pure R and S stereoisomers,as well as other mixtures of the R and S stereoisomers andpharmaceutically acceptable salts thereof. Optical isomers can beobtained in pure form by standard procedures known to those skilled inthe art, which include, but are not limited to, diastereomeric saltformation, kinetic resolution, and asymmetric synthesis. The presentteachings also encompass cis and trans isomers of compounds containingalkenyl moieties (e.g., alkenes and imines). It is also understood thatthe present teachings encompass all possible regioisomers, and mixturesthereof, which can be obtained in pure form by standard separationprocedures known to those skilled in the art, and include, but are notlimited to, column chromatography, thin-layer chromatography, andhigh-performance liquid chromatography.

Pharmaceutically acceptable salts of compounds of the present teachings,which can have an acidic moiety, can be formed using organic andinorganic bases. Both mono and polyanionic salts are contemplated,depending on the number of acidic hydrogens available for deprotonation.Suitable salts formed with bases include metal salts, such as alkalimetal or alkaline earth metal salts, for example sodium, potassium, ormagnesium salts; ammonia salts and organic amine salts, such as thoseformed with norpholine, thiomorpholine, piperidine, pyrrolidine, amono-, di- or tri-lower alkylamine (e.g. ethyl-tert-butyl-, diethyl-,diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-,di-, or trihydroxy lower alkylamine (e.g., mono-, di- ortriethanolamine). Specific non-limiting examples of inorganic basesinclude NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, NaH₂PO₄,Na₂HPO₄, and Na₃PO₄. Internal salts also can be formed. Similarly, whena compound disclosed herein contains a basic moiety, salts can be formedusing organic and inorganic acids. For example, salts can be formed fromthe following acids: acetic, propionic, lactic, benzenesulfonic,benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic,ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic,mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic,pamoic, pantothenic, phosphoric, phthalic, propionic, succinic,sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well asother known pharmaceutically acceptable acids.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence (e.g. in N(R¹³)₂, each R¹³ may bethe same or different than the other). Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The term “neuropsychiatric disorder”, as used herein, is a mental orneurologic disorder which is associated with the nervous system. Forexample, the neuropsychiatric disorder may include anxiety disorders,mood disorders, neurodegenerative disorders, neurodevelopmentaldisorders, autism, pervasive developmental disorder, pain disorders,neuropathic pain, ALS, cognitive disorders, Huntington's disease,Parkinson's disease, supranuclear palsy, frontal temporal dementia,schizophrenia, delirium, Alzheimer's disease, depression, mania,attention deficit disorders, drug addiction, dementia, agitation,apathy, anxiety, psychoses, post-traumatic stress disorders,irritability, and disinhibition, learning disorders, memory loss, mentalretardation, dementia, personality disorders, bipolar disorders, bipolardepression, generalized anxiety disorder, panic disorder,obsessive-compulsive disorders, trichotillomania, eating disorders, andthe like. More specifically, neuropsychiatric disorders includes thoselisted in the Diagnostic and Statistical Manual of Mental Disorders(American Psychiatric Association, 5th Edition): Neurodevelopmentaldisorders, Intellectual disabilities, Intellectual disability(intellectual developmental disorder), Global developmental delay,Unspecified intellectual disability (Intellectual developmentaldisorder), Communication disorders, Language disorder, Speech sounddisorder, Childhood-onset fluency disorder (stuttering), Social(pragmatic) communication disorder, Unspecified communication disorder,Autism spectrum disorder, Rett Syndrome, Attention deficit hyperactivitydisorder (ADHD), Unspecified attention-deficit/Hyperactivity disorder,Specific learning disorder, Motor disorders, Developmental coordinationdisorder, Stereotypic movement disorder, Tic disorders, Tourette'sdisorder, Persistent (Chronic) motor or vocal tic disorder, Provisionaltic disorder, Other specified tic disorder, Unspecified tic disorder,Other neurodevelopmental disorders, Unspecified neurodevelopmentaldisorder, Schizophrenia spectrum and other psychotic disorders,Delusional disorder, Brief psychotic disorder, Schizophreniformdisorder, Schizophrenia, Schizoaffective disorder. Major depressive ormanic mood disorder concurrent with primary symptoms of schizophrenia,Substance/Medication-induced psychotic disorder, Psychotic disorder dueto another medical condition, Catatonia, Other specified schizophreniaspectrum and other psychotic disorder. Unspecified schizophreniaspectrum and other psychotic disorder, Bipolar and related disorders,Anxiety disorders, Obsessive-compulsive and related disorders, Trauma-and stressor-related disorders. Reactive attachment disorder.Disinhibited social engagement disorder. Posttraumatic stress disorder,Acute stress disorder, Adjustment disorder, Other specified Trauma- andstressor-related disorder, Unspecified trauma- and stressor-relateddisorder, Dissociative disorders, Dissociative identity disorder,Dissociative amnesia, Depersonalization/Derealization disorder, Somaticsymptom disorders, Encopresis, other elimination disorder, Disruptive,impulse-control and conduct disorders in DSM-5, Oppositional defiantdisorder, Intermittent explosive disorder, Conduct disorder, Otherspecified disruptive, conduct disorder, unspecified disruptive, andconduct disorder, Substance-Related and Addictive Disorders,Substance-Related Disorders, Alcohol-Related Disorders, Alcohol UseDisorder, Alcohol Withdrawal, Cannabis-Related Disorders, Cannabis UseDisorder, Gambling Disorder, Cluster A personality disorders, Paranoidpersonality disorder, Schizoid personality disorder, Schizotypalpersonality disorder, Cluster B personality disorders, Antisocialpersonality disorder, Borderline personality disorder, Histrionicpersonality disorder, Narcissistic personality disorder, Cluster Cpersonality disorders, Avoidant personality disorder, Dependentpersonality disorder, Obsessive-compulsive personality disorder,Paraphilic disorders.

The term “DSM” refers to a Diagnostic and Statistical Manual of MentalDisorders as provided by American Psychiatric Association's (APA)classification and diagnostic tool. Diagnostic and Statistical Manual ofMental Disorders, Fifth Edition (DSM-5 or DSM-V) is updated in 2013 andexemplary disorders in DSM-V are listed in Appendix A. In addition, theDSM-V has a structure that includes broad categories and subdiagnosesindicating disorders, conditions and problems.

“Neuropsychiatric disorders” could also include neurodegenerative orneurologic disorders including: Alzheimer's disease, dementia, vasculardementia, mixed dementia, Parkinson's disease, Huntington's disease,Amyotrophic lateral sclerosis (ALS), pseudobulbar affect, agitation inAlzheimer's disease, dementia, cerebellar ataxia, hereditary ataxias,multiple sclerosis, Progressive Supranuclear Palsy, pain disorders,neuropathic pain, neuropathies, stroke, seizure, Fragile X, etc.

The neuropsychiatric symptoms may include anxiety, depression, stress,fatigue, feelings of panic, fear, uneasiness, problems in sleeping, coldor sweaty hands and/or feet, shortness of breath, heart palpitations,social phobia, fear of public speaking, an inability to be still andcalm, dry mouth, numbness or tingling in the hands or feet, nausea,muscle tension, dizziness apathy, elation, disinhibition, irritability,wandering, and the like. Additionally, neuropsychiatric symptoms couldinclude: delusions, hallucinations, disorganized thinking or speech,derailment of focal topic or loose associations, incoherence, grosslydisorganized or abnormal motor behavior (including catatonia), negativesymptoms—reduced emotional expression, avolition, alogia, anhedonia,asociality, dyskinesias (including tardive dyskinesia), anhedonia anddysphoria, anger and aggression, or symptoms of dissociation, or somecombination of these.

Other disorders treated could include cancer (including AcuteLymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML),Adrenocortical Carcinoms, Childhood cancers, AIDS-Related Cancers,Kaposi Sarcoma, AIDS-Related Lymphoma, Primary CNS Lymphoma, AnalCancer, Astrocytomas, Atypical Teratoid/Rhabdoid Tumor, Basal CellCarcinoma, Skin Cancer (Nonmelanoma), Bile Duct Cancer, Bladder Cancer,Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and MalignantFibrous Histiocytoma, Brain Stem Glioma, Atypical Teratoid/RhabdoidTumor, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma,Ependymoma, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma,Non-Hodgkin Lymphoma, Carcinoid Tumor, Gastrointestinal Carcinoma,Cardiac (Heart) Tumors, Primary Lymphoma, Cervical Cancer,Cholangiocarcinoma, Chordoma, Chronic Lymphocytic Leukemia (CLL),Chronic Myelogenous Leukemia (CML), Chronic MyeloproliferativeNeoplasms, Colon Cancer, Colorectal Cancer, Craniopharyngioma, CutaneousT-Cell Lymphoma, Mycosis Fungoides and Sézary Syndrome, Ductal CarcinomaIn Situ (DCIS), Embryonal Tumors, Endometrial Cancer, Ependymoma,Esophageal Cancer, Esthesioneuroblastoma, Extracranial Germ Cell Tumor,Extragonadal Germ Cell Tumor, Eye Cancer, Intraocular Melanoma,Retinoblastoma, Fallopian Tube Cancer, Fibrous Histiocytoma of Bone,Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach)Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal StromalTumors (GIST), Germ Cell Tumor, Ovarian, Testicular, GestationalTrophoblastic Disease, Glioma, Hairy Cell Leukemia, Head and NeckCancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell,Hodgkin Lymphoma, Hypopharyngeal Cancer, Islet Cell Tumors, PancreaticNeuroendocrine Tumors, Kaposi Sarcoma, Kidney, Renal Cell, Wilms Tumor,Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, AcuteLymphoblastic (ALL), Acute Myeloid (AML), Chronic Lymphocytic (CLL),Chronic Myelogenous (CML), Hairy Cell, Lip and Oral Cavity Cancer, LiverCancer (Primary), Lung Cancer, Non-Small Cell, Small Cell, Lymphoma,Hodgkin, Non-Hodgkin, Macroglobulinemia, Waldenström, Male BreastCancer, Melanoma, Merkel Cell Carcinoma, Mesothelioma, MetastaticSquamous Neck Cancer with Occult Primary, Midline Tract CarcinomaInvolving NUT Gene, Mouth Cancer, Multiple Endocrine NeoplasiaSyndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides,Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms,Myelogenous Leukemia, Chronic (CML), Myeloid Leukemia, Acute (AML)Myeloma, Multiple, Myeloproliferative Neoplasms, Nasal Cavity andParanasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma,Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, OralCavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and MalignantFibrous Histiocytoma of Bone, Ovarian Cancer, Low Malignant PotentialTumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet CellTumors), Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal CavityCancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer,Pheochmmocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma,Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary CentralNervous System (CNS) Lymphoma, Primary Peritoneal Cancer, ProstateCancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis andUreter, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma,Salivary Gland Cancer, Rhabdomyosarcoma, Uterine, Small IntestineCancer, Soft Tissue Sarcoma, Sqamous Cell Carcinoma, Squamous NeckCancer with Occult Primary, Metastatic, Ttomach (Gastric) Cancer, T-CellLymphoma, Testicular Cancer, Throat Cancer, Thymoma and ThymicCarcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvisand Ureter, Unknown Primary, Ureter and Renal Pelvis, Transitional CellCancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma,Vaginal Cancer, Vulvar Cancer, Waldenström Macroglobulinemia, WilmsTumor.

The term “treatment” as used herein includes any treatment of acondition or disease in a subject, or particularly a human, and mayinclude: (i) preventing the disease or condition from occurring in thesubject which may be predisposed to the disease but has not yet beendiagnosed as having it; (ii) inhibiting the disease or condition, i.e.,arresting its development; relieving the disease or condition, i.e.,causing regression of the condition: or (iii) ameliorating or relievingthe conditions caused by the disease, i.e., symptoms of the disease.“Treatment” could be in combination with other standard therapies oralone.

As used herein, “therapeutically effective” and “effective dose” referto a substance or an amount that elicits a desirable biological activityor effect.

As used herein, the term “riluzole prodrug” shall mean a compound thatare cleaved to release riluzole in the plasma via either an enzymatic orgeneral biophysical release process.

As used herein, the term “prodrug agent” shall mean a compound that arecleaved to release riluzole in the plasma via either an enzymatic orgeneral biophysical release process.

As used herein, the term “anticancer agent” shall mean a compound thatis useful for the treatment or prevention of cancer, including but notlimited to melanoma, ovarian cancer, cervical cancer, breast cancer,prostate cancer, testicular cancer, lung cancer, renal cancer,colorectal cancer, skin cancer, brain cancer, and leukemia.

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryembodiment of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat may be associated with the targeted or suspected disease orcondition. These and other routine methods allow the clinician to selectpatients in need of therapy using the methods and compounds of thepresent invention.

The Prodrug Agents:

The prodrug agents of the present invention are N-substituted riluzoleanalogs, and include all enantiomeric and diasteromeric forms andpharmaceutically accepted salts thereof having the formula (I):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof, wherein: R¹ is selected from the group consisting ofC₁-C₆ fluoroalkyl, OR², (CR^(6a)R^(6b))_(m)NHR⁷, CR^(10a)R^(10b)NR¹¹R¹²,

R² is selected from the group consisting of CH₂(CH₂)_(n)NR^(3a)R^(3b),

R^(3a) and R^(3b) are independently selected from the group consistingof hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, and CO₂R⁴;R^(3a) and R^(3b) cannot both be C₁-C₆ alkyl;R^(3a) and R^(3b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedheterocyclic ring consisting of two to five carbon atoms and a memberselected from the group consisting of O, NR⁵, S, and SO₂;n is 1 or 2;R⁴ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branchedalkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionallysubstituted phenyl, and optionally substituted benzyl;R⁵ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branchedalkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R^(6a) and R^(6b) are at each occurrence independently selected from thegroup consisting of hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₇ branched alkyl, optionally substitutedC₂-C₆ alkenyl, optionally substituted C₁-C₆ alkynyl, and optionallysubstituted C₃-C₇ cycloalkyl;R^(6a) and R^(6b) are taken together with the atom to which they arebound to form an optionally substituted 6 membered ring;m is 1, 2, or 3;R⁷ is selected from the group consisting of COC R^(8a)R^(8b)(NHR⁹),

R^(8a) and R^(8b) are at each occurrence independently selected from thegroup consisting of hydrogen, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂OH, CH(OH)CH₃, CH₂Ph, CH₂(4-OH-Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH,CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, andCH₂CH₂CONH₂;R⁹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;Y is at each occurrence independently selected from the group consistingof H₂ or O:R^(10a) and R^(10b) are at each occurrence independently selected fromthe group consisting of hydrogen·CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH(O)CH₃, CH₂Ph, CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂(CCH),CH₂(cyclohexyl), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂;R^(10a) and R^(10b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedcarbocyclic ring;R¹¹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, and C₂-C₆ alkynyl;R^(10a) and R¹¹ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom, and R¹² is not hydrogen;R^(10b) and R¹¹ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom, and R¹² is not hydrogen;R¹² is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, COCR^(13a)R^(13b)NR^(15a)R^(15b),COCR^(13a)R^(13b)OR¹⁴, SO₂CR^(13a)R^(13b)NR^(15a)R^(15b),COCR^(13a)R^(13b)NHSO₂R^(15a),

and (CR^(19a)R^(19b))_(q)NHR²⁰, and when R¹² is hydrogen, R¹¹ cannot behydrogen;R¹¹ and R¹² are taken together with the atom to which they are bound toform an optionally substituted four to six membered saturatedheterocyclic ring containing a nitrogen atom and optionally containingan additional heteroatom from the group consisting of N and O;R^(13a) and R^(13b) are at each occurrence independently selected fromthe group consisting hydrogen, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CCH, CH(CH₃)₂,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH₂CH₂OCH_(z)Ph,CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph), (CH₂)₄NH₂,(CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H,CH₂CONH₂, and CH₂CH₂CONH₂;R^(13a) and R^(13b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedcarbocyclic ring;R^(13a) and R^(13b) are taken together with the atom to which they arebound to form an optionally substituted six membered saturatedheterocyclic ring with one O atom within the ring;R^(13a) and R¹⁴ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom;R^(13a) and R^(15a) are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom;Y¹ is at each occurrence independently selected from the groupconsisting of H₂, O, and —H/—OCH₂Ph;R¹⁴ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R^(15a) and R^(15b) are at each occurrence independently selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ fluoroalkyl, COR²¹,CH₂R²¹, SO₂R²², an optionally substituted four to six membered saturatedheterocyclic ring containing a heteroatom selected from the groupconsisting of NR²⁴ and O, COCHR²³NH₂,

R^(15a) and R^(15b) are taken together with the atom to which they arebound to form an optionally substituted four to six membered saturatedheterocyclic ring optionally containing one O atom within the ring;R¹⁶ is at each occurrence independently selected from the groupconsisting of CH₂, O, C═O, and NH;R¹⁷ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R¹⁸ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R¹⁷ and R¹⁸ are taken together with the atoms to which they are bound toform an optionally substituted five or six membered ring containing twonitrogen atoms;R^(19a) and R^(19b) are at each occurrence independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₇ branched alkyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted C₂-C₆ alkenyl, and optionallysubstituted C₂-C₆ alkynyl;R^(19a) and R^(19b) are taken together with the atom to which they arebound to form an optionally substituted 3 to 6 membered carbocyclicring;R²⁰ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;q is 1, or 2;R²¹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ fluoroalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl;R²² is at each occurrence independently selected from the groupconsisting of C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl optionally substituted aryl, optionallysubstituted heteroaryl;R²³ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CHOOCH₂Ph,CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H,CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂;R²⁴ is at each occurrence independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, COR²⁵, and SO₂—C₁₋₆alkyl;R²⁵ is at each occurrence independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, C₁-C₆alkoxy, and C₁-C₆ alkylamino.

The compounds of the present invention include compounds having formula(II):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(III):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(IV):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(V):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VI):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VI):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VIII):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(IX):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(X):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XI):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XII):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XIII):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XIV):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XV):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVI):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVII):

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVIII)

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof, wherein:R²³ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph,CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H,CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂.

In some embodiments R¹ is C₁-C₆ fluoroalkyl.

In some embodiments R¹ is OR².

In some embodiments R¹ is (CR^(6a)R^(6b))_(m)NHR⁷.

In some embodiments R¹ is CR^(10a)R^(10b)NR¹¹R¹².

In some embodiments R¹ is

In some embodiments R¹ is

In some embodiments R¹ is

In some embodiments R² is CH₂(CH₂)_(n)NR^(3a)R^(3b).

In some embodiments R² is

In some embodiments R^(3a) is hydrogen.

In some embodiments R^(3a) is C₁-C₆ alkyl.

In some embodiments R^(3a) is C₃-C₇ cycloalkyl.

In some embodiments R^(3a) is C₃-C₇ branched alkyl.

In some embodiments R^(3a) is C₂-C₆ alkenyl.

In some embodiments R^(3a) is C₂-C₆ alkynyl.

In some embodiments R^(3a) is CO₂R⁴.

In some embodiments R^(3b) is hydrogen.

In some embodiments R^(3b) is C₁₋₆ alkyl.

In some embodiments R^(3b) is C₃-C₇ cycloalkyl.

In some embodiments R^(3b) is C₃-C₇ branched alkyl.

In some embodiments R^(3b) is C₂-C₆ alkenyl.

In some embodiments R^(3b) is C₂-C₆ alkynyl.

In some embodiments R^(3b) is CO₂R⁴.

In some embodiments R^(3a) and R^(3b) are taken together with the atomto which they are bound to form an optionally substituted three to sixmembered saturated heterocyclic ring consisting of two to five carbonatoms and a member selected from the group consisting of O, NR⁵, S, andSO₂;

In some embodiments n is 1.

In some embodiments n is 2.

In some embodiments R⁴ is C₁-C₆ alkyl.

In some embodiments R⁴ is C₃-C₇ branched alkyl.

In some embodiments R⁴ is C₃-C₇ cycloalkyl.

In some embodiments R⁴ is C₂-C₆ alkenyl.

In some embodiments R⁴ is C₂-C₆ alkynyl.

In some embodiments R⁴ is optionally substituted phenyl.

In some embodiments R⁴ is benzyl.

In some embodiments R⁵ is C₁-C₆ alkyl

In some embodiments R⁵ is C₃-C₇ branched alkyl

In some embodiments R⁵ is C₃-C₇ cycloalkyl.

In some embodiments R⁵ is C₂-C₆ alkenyl.

In some embodiments R⁵ is C₂-C₆ alkynyl.

In some embodiments R^(6a) is hydrogen.

In some embodiments R^(6a) is optionally substituted C₁-C₆ alkyl.

In some embodiments R^(6a) is optionally substituted C₃-C₇ branchedalkyl.

In some embodiments R^(6a) is optionally substituted C₃-C₇ cycloalkyl.

In some embodiments R^(6a) is optionally substituted C₂-C₆ alkenyl.

In some embodiments R^(6a) is optionally substituted C₂-C₆ alkynyl.

In some embodiments R^(6b) is hydrogen.

In some embodiments R^(6b) is optionally substituted C₁-C₆ alkyl.

In some embodiments R^(6b) is optionally substituted C₃-C₇ branchedalkyl.

In some embodiments R^(6b) is optionally substituted C₃-C₇ cycloalkyl.

In some embodiments R^(6b) is optionally substituted C₂-C₆ alkenyl.

In some embodiments R^(6b) is optionally substituted C₂-C₆ alkynyl.

In some embodiments R^(6a) and R^(6b) are taken together with the atomto which they are bound to form an optionally substituted 6 memberedring.

In some embodiments m is 1.

In some embodiments m is 2.

In some embodiments m is 3.

In some embodiments R⁷ is COC R^(8a)R^(8b)(NHR⁹).

In some embodiments R⁷ is

In some embodiments R⁷ is

In some embodiments R^(8a) is hydrogen.

In some embodiments R^(8a) is CH₃.

In some embodiments R^(8a) is CH(CH₃)₂.

In some embodiments R^(8a) is CH₂CH(CH₃)₂.

In some embodiments R^(8a) is CH(CH₃)CH₂CH₃.

In some embodiments R^(8a) is CH₂OH.

In some embodiments R^(8a) is CH(OH)CH₃.

In some embodiments R^(8a) is CH₂Ph.

In some embodiments R^(8a) is CH₂(4-OH-Ph).

In some embodiments R^(8a) is (CH₂)₄NH₂.

In some embodiments R^(8a) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(8a) is CH₂(3-indole).

In some embodiments R^(8a) is CH₂(5-imidazole).

In some embodiments R^(8a) is CH₂CO₂H.

In some embodiments R^(8a) is CH₂CH₂CO₂H.

In some embodiments R^(8a) is CH₂CONH₂.

In some embodiments R^(8a) is CH₂CH₂CONH₂.

In some embodiments R^(8b) is hydrogen.

In some embodiments R^(8b) is CH₃.

In some embodiments R^(8b) is CH(CH₃)₂.

In some embodiments R^(8b) is CH₂CH(CH₃)₂.

In some embodiments R^(8b) is CH(CH₃)CH₂CH₃.

In some embodiments R^(8b) is CH₂OH.

In some embodiments R^(8b) is CH(OH)CH₃.

In some embodiments R^(8b) is CH₂Ph.

In some embodiments R^(8b) is CH₂(4-OH-Ph).

In some embodiments R^(8b) is (CH₂)₄NH₂.

In some embodiments R^(8b) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(8b) is CH₂(3-indole).

In some embodiments R^(8b) is CH₂(5-imidazole).

In some embodiments R^(8b) is CH₂CO₂H.

In some embodiments R^(8b) is CH₂CH₂CO₂H.

In some embodiments R^(8b) is CH₂CONH₂.

In some embodiments R^(8b) is CH₂CH₂CONH₂.

In some embodiments R⁹ is hydrogen.

In some embodiments R⁹ is C₁-C₆ alkyl.

In some embodiments R⁹ is C₃-C₇ branched alkyl.

In some embodiments R⁹ is C₃-C₇ cycloalkyl.

In some embodiments R⁹ is C₂-C₆ alkenyl.

In some embodiments R⁹ is C₂-C₆ alkynyl.

In some embodiments Y is H₂.

In some embodiments Y is O.

In some embodiments R^(10a) is hydrogen.

In some embodiments R^(10a) is CH₃.

In some embodiments R^(10a) is CH₂CH₃.

In some embodiments R^(10a) is CH(CH₃)₂.

In some embodiments R^(10a) is CH₂CH(CH₃)₂.

In some embodiments R^(10a) is CH(CH₃)CH₂CH₃.

In some embodiments R^(10a) is CH₂OH.

In some embodiments R^(10a) is CH₂OCH₂Ph.

In some embodiments R^(10a) is CH(OH)CH₃.

In some embodiments R^(10a) is CH₂Ph.

In some embodiments R^(10a) is CH₂(4-OH-Ph).

In some embodiments R^(10a) is (CH₂)₄NH₂.

In some embodiments R^(10a) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(10a) is CH₂(3-indole).

In some embodiments R^(10a) is CH₂(5-imidazole).

In some embodiments R^(10a) is CH₂(CCH).

In some embodiments R^(10a) is CH₂(cyclohexyl),

In some embodiments R^(10a) is CH₂CO₂H.

In some embodiments R^(10a) is CH₂CH₂CO₂H.

In some embodiments R^(10a) is CH₂CONH₂.

In some embodiments R^(10a) is CH₂CH₂CONH₂.

In some embodiments R^(10b) is hydrogen.

In some embodiments R^(10b) is CH₃.

In some embodiments R^(10b) is CH₂CH₃.

In some embodiments R^(10b) is CH(CH₃)₂.

In some embodiments R^(10b) is CH₂CH(CH₃)₂.

In some embodiments R^(10b) is CH(CH₃)CH₂CH.

In some embodiments R^(10b) is CH₂OH.

In some embodiments R^(10b) is CH₂OCH₂Ph.

In some embodiments R^(10b) is CH(OH)CH₃.

In some embodiments R^(10b) is CH₂Ph.

In some embodiments R^(10b) is CH₂(4-OH-Ph).

In some embodiments R^(10b) is (CH₂)₄NH₂.

In some embodiments R^(10b) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(10b) is CH₂(3-indole).

In some embodiments R^(10b) is CH₂(5-imidazole).

In some embodiments R^(10b) is CH₂(CCH).

In some embodiments R^(10b) is CH₂(cyclohexyl),

In some embodiments R^(10b) is CH₂CO₂H.

In some embodiments R^(10b) is CH₂CH₂CO₂H.

In some embodiments R^(10b) is CH₂CONH₂.

In some embodiments R^(10b) is CH₂CH₂CONH₂.

In some embodiments R^(10a) and R^(10b) are taken together with the atomto which they are bound to form an optionally substituted three to sixmembered saturated carbocyclic ring.

In some embodiments R¹¹ is hydrogen.

In some embodiments R¹¹ is of C₁-C₆ alkyl.

In some embodiments R¹¹ is C₃-C₇ branched alkyl,

In some embodiments R¹¹ is C₃-C₇ cycloalkyl,

In some embodiments R¹¹ is C₂-C₆ alkenyl.

In some embodiments R¹¹ is C₁-C₆ haloalkyl.

In some embodiments R¹¹ is C₂-C₆ alkynyl,

In some embodiments R^(10a) and R¹¹ are taken together with the atoms towhich they are bound to form an optionally substituted four to sixmembered ring containing one nitrogen atom, and R¹² is not hydrogen.

In some embodiments R^(10b) and R¹¹ are taken together with the atoms towhich they are bound to form an optionally substituted four to sixmembered ring containing one nitrogen atom, and R¹² is not hydrogen.

In some embodiments R¹² is hydrogen.

In some embodiments R¹² is C₁-C₆ alkyl,

In some embodiments R¹² is COCR^(13a)R^(13b) NR^(15a)R^(15b).

In some embodiments R¹² is COCR^(13a)R^(13b)OR¹⁴.

In some embodiments R¹² is SO₂CR^(13a)R^(13b)NR^(15a)R^(15b).

In some embodiments R¹² is COCR_(13a)R^(13b)NHSO₂R^(15a).

In some embodiments R¹² is

In some embodiments R¹² is

In some embodiments R¹² is

In some embodiments R¹² is

In some embodiments R¹²

In some embodiments R¹² is

In some embodiments R¹² is

In some embodiments R¹² is (CR^(19a)R^(19b))_(q)NHR²⁰.

In some embodiments R¹¹ and R¹² are taken together with the atom towhich they are bound to form an optionally substituted four to sixmembered saturated heterocyclic ring containing a nitrogen atom andoptionally containing an additional heteroatom from the group consistingof N and O.

In some embodiments R^(13a) is hydrogen.

In some embodiments R^(13a) is CH₃.

In some embodiments R^(13a) is CH₂CH₃.

In some embodiments R^(13a) is CH₂CH₂CH₃,

In some embodiments R^(13a) is CH₂CCH.

In some embodiments R^(13a) is CH(CH₃)₂.

In some embodiments R^(13a) is CH₂CH(CH₃)₂.

In some embodiments R^(13a) is CH(CH₃)CH₂CH₃.

In some embodiments R^(13a) is CH₂OH.

In some embodiments R^(13a) is CH₂OCH₂Ph.

In some embodiments R^(13a) is CH₂CH₂OCH₂Ph.

In some embodiments R^(13a) is CH(OH)CH₃.

In some embodiments R^(13a) is CH₂Ph.

In some embodiments R^(13a) is CH₂(cyclohexyl).

In some embodiments R^(13a) is CH₂(4-OH-Ph).

In some embodiments R^(13a) is (CH₂)₄NH₂.

In some embodiments R^(13a) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(13a) is CH₂(3-indole).

In some embodiments R^(13a) is CH₂(5-imidazole).

In some embodiments R^(13a) is CH₂CO₂H.

In some embodiments R^(13a) is CH₂CH₂CO₂H.

In some embodiments R^(13a) is CH₂CONH₂.

In some embodiments R^(13a) is CH₂CH₂CONH₂.

In some embodiments R^(13b) is hydrogen.

In some embodiments R^(13b) is CH₃.

In some embodiments R^(13b) is CH₂CH₃.

In some embodiments R^(13b) is CH₂CH₂CH₃.

In some embodiments R^(13b) is CH₂CCH.

In some embodiments R^(13b) is CH(CH₃)₂.

In some embodiments R^(13b) is CH₂CH(CH₃)₂.

In some embodiments R^(13b) is CH(CH₃)CH₂CH₃.

In some embodiments R^(13b) is CH₂OH.

In some embodiments R^(13b) is CH₂OCH₂Ph.

In some embodiments R^(13b) is CH₂CH₂OCH₂Ph.

In some embodiments R^(13b) is CH(OH)CH₃.

In some embodiments R^(13b) is CH₂Ph.

In some embodiments R^(13b) is CH₂(cyclohexyl).

In some embodiments R^(13b) is CH₂(4-OH-Ph).

In some embodiments R^(13b) is (CH₂)₄NH₂.

In some embodiments R^(13b) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(13b) is CH₂(3-indole).

In some embodiments R^(13b) is CH₂(5-imidazole).

In some embodiments R^(13b) is CH₂CO₂H.

In some embodiments R^(13b) is CH₂CH₂CO₂H.

In some embodiments R^(13b) is CH₂CONH₂.

In some embodiments R^(13b) is CH₂CH₂CONH₂.

In some embodiments R^(13a) and R^(13b) are taken together with the atomto which they are bound to form an optionally substituted three to sixmembered saturated carbocyclic ring.

In some embodiments R^(13a) and R^(13b) are taken together with the atomto which they are bound to form an optionally substituted six memberedsaturated heterocyclic ring with one O atom within the ring.

In some embodiments R^(13a) and R¹⁴ are taken together with the atoms towhich they are bound to form an optionally substituted four to sixmembered ring containing one nitrogen atom.

In some embodiments R^(13a) and R^(15a) are taken together with theatoms to which they are bound to form an optionally substituted four tosix membered ring containing one nitrogen atom. In some embodiments Y¹is

In some embodiments Y¹ is H₂.

In some embodiments Y¹ is O.

In some embodiments Y¹ is —H/—OCH₂Ph.

In some embodiments R¹⁴ is hydrogen.

In some embodiments R¹⁴ is C₁-C₆ alkyl.

In some embodiments R¹⁴ is C₃-C₇ branched alkyl.

In some embodiments R¹⁴ is C₃-C₇ cycloalkyl.

In some embodiments R¹⁴ is C₂-C₆ alkenyl.

In some embodiments R¹⁴ is C₂₋₆ alkynyl.

In some embodiments R^(15a) is hydrogen.

In some embodiments R^(15a) is C₁-C₆ alkyl.

In some embodiments R^(15a) is C₃-C₇ branched alkyl.

In some embodiments R^(15a) is C₃-C₇ cycloalkyl.

In some embodiments R^(15a) is C₂-C₆ alkenyl.

In some embodiments R^(15a) is C₂-C₆ alkynyl.

In some embodiments R^(15a) is C₁-C₆ fluoroalkyl.

In some embodiments R^(15a) is COR²¹.

In some embodiments R^(15a) is CH₂R²¹.

In some embodiments R^(15a) is SO₂R²².

In some embodiments R^(15a) is an optionally substituted four to sixmembered saturated heterocyclic ring containing a heteroatom selectedfrom the group consisting of NR²⁴ and O,

In some embodiments R^(15a) is COCHR²³NH₂.

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15b) is C₁-C₆ alkyl.

In some embodiments R^(15b) is C₃-C₇ branched alkyl.

In some embodiments R^(15b) is C₃-C₇ cycloalkyl.

In some embodiments R^(15b) is C₂-C₆ alkenyl.

In some embodiments R^(15b) is C₂-C₆ alkynyl.

In some embodiments R^(15b) is C₁-C₆ fluoroalkyl.

In some embodiments R^(15b) is COR²¹.

In some embodiments R^(15b) is CH₂R²¹.

In some embodiments R^(13b) is SO₂R²².

In some embodiments R^(15b) is an optionally substituted four to sixmembered saturated heterocyclic ring containing a heteroatom selectedfrom the group consisting of NR²⁴ and O,

In some embodiments R^(15b) is COCHR²³NH₂.

In some embodiments R^(15b) is CF₃.

In some embodiments R^(15b) is

In some embodiments R^(15b) is CHF

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15a) and R^(15b) are taken together with the atomto which they are bound to form an optionally substituted four to sixmembered saturated heterocyclic ring optionally containing one O atomwithin the ring.

In some embodiments R¹⁶ is CH₂.

In some embodiments R¹⁶ is O.

In some embodiments R¹⁶ is C═O.

In some embodiments R¹⁶ is NH.

In some embodiments R¹⁷ is hydrogen.

In some embodiments R¹⁷ is C₁-C₆ alkyl.

In some embodiments R¹⁷ is C₃-C₇ branched alkyl.

In some embodiments R¹⁷ is C₃-C₇ cycloalkyl.

In some embodiments R¹⁷ is C₂-C₆ alkenyl.

In some embodiments R¹⁷ is C₂-C₆ alkynyl.

In some embodiments R¹⁸ is hydrogen.

In some embodiments R¹⁸ is C₁-C₆ alkyl.

In some embodiments R¹⁸ is C₃-C₇ branched alkyl.

In some embodiments R¹⁸ is C₃-C₇ cycloalkyl.

In some embodiments R¹⁸ is C₂-C₆ alkenyl.

In some embodiments R¹⁸ is C₂-C₆ alkynyl.

In some embodiments R¹⁷ and R¹⁸ are taken together with the atoms towhich they are bound to form an optionally substituted five or sixmembered ring containing two nitrogen atoms.

In some embodiments R^(19a) is hydrogen.

In some embodiments R^(19a) is optionally substituted C₁-C₆ alkyl.

In some embodiments R^(19a) is optionally substituted C₃-C₇ branchedalkyl.

In some embodiments R^(19a) is optionally substituted C₃-C₇ cycloalkyl.

In some embodiments R^(19a) is optionally substituted C₂-C₆ alkenyl.

In some embodiments R^(19a) is optionally substituted C₁-C₆ alkynyl.

In some embodiments R^(19b) is hydrogen.

In some embodiments R^(19b) is optionally substituted C₁-C₆ alkyl.

In some embodiments R^(19b) is optionally substituted C₃-C₇ branchedalkyl.

In some embodiments R^(19b) is optionally substituted C₃-C₇ cycloalkyl.

In some embodiments R^(19b) is optionally substituted C₂-C₆ alkenyl.

In some embodiments R^(19b) is optionally substituted C₂-C₆ alkynyl.

In some embodiments R^(19a) and R^(19b) are taken together with the atomto which they are bound to form an optionally substituted 3 memberedcarbocyclic ring.

In some embodiments R^(19a) and R^(19b) are taken together with the atomto which they are bound to form an optionally substituted 4 memberedcarbocyclic ring.

In some embodiments R^(19a) and R^(19b) are taken together with the atomto which they are bound to form an optionally substituted 5 memberedcarbocyclic ring.

In some embodiments R^(19a) and R^(19b) are taken together with the atomto which they are bound to form an optionally substituted 6 memberedcarbocyclic ring.

In some embodiments R²⁰ is hydrogen.

In some embodiments R²⁰ is C₁-C₆ alkyl.

In some embodiments R²⁰ is C₃-C₇ branched alkyl.

In some embodiments R²⁰ is C₃-C₇ cycloalkyl.

In some embodiments R²⁰ is C₂-C₆ alkenyl.

In some embodiments R²⁰ is C₂-C₆ alkynyl.

In some embodiments q is 1.

In some embodiments q is 2.

In some embodiments R²¹ is hydrogen.

In some embodiments R²¹ is C₂-C₆ alkyl.

In some embodiments R²¹ is C₃-C₇ branched alkyl.

In some embodiments R²¹ is C₃-C₇ cycloalkyl.

In some embodiments R²¹ is C₂-C₆ alkenyl.

In some embodiments R²¹ is C₂-C₆ alkynyl.

In some embodiments R²¹ is C₁-C₆ fluoroalkyl.

In some embodiments R²¹ is optionally substituted aryl.

In some embodiments R²¹ is optionally substituted heteroaryl.

In some embodiments R²² is C₁-C₆ alkyl.

In some embodiments R²² is C₃-C₇ branched alkyl.

In some embodiments R²² is C₃-C₇ cycloalkyl.

In some embodiments R²² is C₁-C₆ alkenyl.

In some embodiments R²² is C₁-C₆ alkynyl.

In some embodiments R²² is optionally substituted aryl.

In some embodiments R²² is optionally substituted heteroaryl

In some embodiments R²³ is hydrogen.

In some embodiments R²³ is CH₃.

In some embodiments R²³ is CH₂CH₃.

In some embodiments R²³ is CH₂CH₂CH₃.

In some embodiments R²³ is CH₂CCH.

In some embodiments R²³ is CH(CH₃)₂.

In some embodiments R²³ is CH₂CH(CH₃)₂.

In some embodiments R²³ is CH(CH₃)CH₂CH₃.

In some embodiments R²³ is CH₂OH.

In some embodiments R²³ is CH₂OCH₂Ph.

In some embodiments R²³ is CH₂CH₂OCH₂Ph.

In some embodiments R²³ is CH(OH)CH₃.

In some embodiments R²³ is CH₂Ph.

In some embodiments R²³ is CH₂(cyclohexyl).

In some embodiments R²³ is CH₂(4-OH-Ph).

In some embodiments R²³ is (CH₂)₄NH₂.

In some embodiments R²³ is (CH₂)₃NHC(NH₂)NH.

In some embodiments R²³ is CH₂(3-indole).

In some embodiments R²³ is CH₂(5-imidazole).

In some embodiments R²³ is CH₂CO₂H.

In some embodiments R²³ is CH₂CH₂CO₂H.

In some embodiments R²³ is CH₂CONH₂.

In some embodiments R²³ is CH₂CH₂CONH₂.

In some embodiments R²⁴ is hydrogen.

In some embodiments R²⁴ is C₁-C₆ alkyl.

In some embodiments R²⁴ is C₃-C₇ branched alkyl.

In some embodiments R²⁴ is C₃-C₇ cycloalkyl.

In some embodiments R²⁴ is C₂-C₆ alkenyl.

In some embodiments R²⁴ is C₂-C₆ alkynyl.

In some embodiments R²⁴ is optionally substituted aryl.

In some embodiments R²⁴ is optionally substituted heteroaryl.

In some embodiments R²⁴ is COR²⁵.

In some embodiments R²⁴ is SO₂C₁₋₆alkyl.

In some embodiments R²⁵ is hydrogen.

In some embodiments R²⁵ is C₁-C₆ alkyl.

In some embodiments R²⁵ is C₃-C₇ branched alkyl.

In some embodiments R²⁵ is C₃-C₇ cycloalkyl.

In some embodiments R²⁵ is C₂-C₆ alkenyl.

In some embodiments R²⁵ is C₂-C₆ alkynyl.

In some embodiments R²⁵ is optionally substituted aryl.

In some embodiments R²⁵ is optionally substituted heteroaryl.

In some embodiments R²⁵ is C₁-C₆ alkoxy.

In some embodiments R²⁵ is C₁-C₆ alkylamino.

Exemplary non-limiting embodiments of the invention include

-   2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide;-   (R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)amino)ethyl)propanamide:-   3-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) propanamide;-   1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) cyclopropane-1-carboxamide;-   (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)azetidine-2-carboxamide;-   2-amino-2-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (S)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (R)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (R)-2-amino-3-hydroxy-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)pent-4-ynamide;-   (S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)pent-4-ynamide;-   (R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide;-   1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)amino)ethyl)cyclobutane-1-carboxamide;-   (S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)pentanamide;-   (R)-2-amino-3-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide;-   (S)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide;-   (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide;-   (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide;-   (R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide;-   (R)-2-amino-4-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanamide;-   (R)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide;-   4-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)tetrahydro-2H-pyran-4-carboxamide;-   (R)-2-amino-N1-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)pentanediamide;-   (R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)-3-phenylpropanamide;-   (R)-2-amino-3-cyclohexyl-N-(2-oxo-2-((6-(trifluoro methoxy)benzo[d]    thiazol-2-yl)amino)ethyl)propanamide;-   (R)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (S)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (R)-2-amino-3-(1H-indol-3-yl)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (2S,4R)-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide;-   (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide;-   (R)-2-amino-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide;-   (R)-1-(N,N-dimethyl-L-valyl)-N-(6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(L-valyl)-N-(6-4-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-D-valyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)    pyrrolidine-2-carboxamide;-   (R)-1-glycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-N-ethylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)    pyrrolidine-2-carboxamide;-   (R)-1-N-isopropylglycinyl-N-(6-(trifluoromethoxy)    benzo[d]thiazol-2-yl) pyrrolidine-2-carboxamide;-   (R)-1-N-t-butylglycinyl-N-(6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(1-aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(1-aminomethyl)cyclohexane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(D-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(D-alanyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(ethylglycyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(isopropylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(tert-butylglycyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(D-leucyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide;-   (S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)azetidine-2-carboxamide;-   (S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide;-   (S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide;-   (S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-1-carboxamide;-   (S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)piperidine-2-carboxamide;-   (S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)piperidine-2-carboxamide;-   (R)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)piperidine-2-carboxamide;-   1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)cyclopropane-1-carboxamide;-   1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide;-   1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)cyclobutane-1-carboxamide;-   1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   1-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)    cyclopentane-1-carboxamide;-   1-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   1-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)    cyclohexane-1-carboxamide;-   (R)-1-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)cyclobutane-1-carboxamide;-   (R)-1-(2-amino-3-methylbutanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-arboxamide;-   (S)-2-(2-aminoacetamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-2-(2-(methylamino)acetamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-2-((R)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-2-((S)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)propanamide;-   (R)-2-amino-3-methyl-N—((S)-1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)butanamide;-   (S)-2-amino-2-methyl-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide;-   (S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamide;-   (S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutane-1-carboxamide;-   1-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   (R)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   2-(2-aminoacetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (R)-2-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)propan-2-yl)-3-phenylpropanamide;-   (S)-2-amino-3-(benzyloxy)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide;-   1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-arboxamide;-   1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutane-1-carboxamide;-   2-amino-2-methyl-N-(2-methyl-1-oxo-1-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide;-   3-amino-2,2-dimethyl-N-(2-methyl-1-oxo-1-((6-trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide:-   1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamide;-   1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopentane-1-carboxamide;-   1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclohexane-1-carboxamide;-   2-methyl-2-(2-(methylamino)acetamido)-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)propanamide;-   2-(2-(ethylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   2-(2-(isopropylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide,-   2-(2-(tert-butylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-2-(2-aminoacetamido)-N-(6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)propanamide;-   (S)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)amino)propan-2-yl)propanamide;-   (R)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)propan-2-yl)propanamide;-   3-Amino-N,2,2-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopropane-1-carboxamide;-   1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopentane-1-carboxamide;-   1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexane-1-carboxamide;-   N-methyl-2-(methylamino)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(tert-butylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)acetamide;-   2-(dimethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)    amino)ethyl)acetamide;-   2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) ethyl)acetamide;-   (S)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) ethyl)propanamide;-   (R)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)    ethyl)propanamide;-   3-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)amino)ethyl) propanamide;-   2-amino-N-ethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)amino) ethyl)acetamide;-   2-amino-N-isopropyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(aminomethyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)benzamide;-   tert-butyl    (4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)carbamate;-   4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide;-   (S)—N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)    pyrrolidine-2-carboxamide;-   (S)-2-amino-4-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) butyl)pentanamide;-   4-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)butanamide;-   (S)-4-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)butanamide;-   (S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) butyl)butanamide;-   (S)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)    pyrrolidine-2-carboxamide;-   (2S,3S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)    amino)butyl)pentanamide;-   (S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)amino)butyl) amino)pentanoic acid;-   (S)-2-amino-4-(methylthio)-N-(4-oxo-4-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide;-   (S)-4-(2-amino-3-phenylpropanamido)-N-(6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)butanamide;-   (S)-3-amino-4-oxo-4-((4-oxo-4-((6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)amino) butyl)amino)butanoic acid;-   (S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)butyl) amino)pentanoic acid;-   (S)-4-(2-amino-3-(1H-indol-3-yl)propanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide;-   (S)—N-(1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)    methyl)pyrrolidine-2-cart)oxamide;-   (S)-N-(1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)    ethyl)cyclohexyl) methyl)pyrrolidine-2-carboxamide;-   (S)-2-amino-4-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)-   ethyl)cyclohexyl)methyl)pentanamide;-   (S)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide;-   2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)    ethyl) cyclohexyl)methyl)acetamide;-   (S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)    cyclohexyl)methyl)propanamide;-   2-(methylamino)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl) cyclohexyl)methyl)acetamide;-   (R)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)-   ethyl)cyclohexyl)methyl)butanamide;-   (S)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)    cyclohexyl)methyl)pyrrolidine-2-carboxamide;-   (S)-2-amino-N1-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)amino)ethyl) cyclohexyl)methyl)pentanediamide;-   (S)-2-amino-4-(methylthio)-N-((1-(2-oxo-2-((6-trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide;-   (S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) cyclohexyl)methyl)-3-phenylpropanamide;-   (S)-3-amino-4-oxo-4-(((1-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) ethyl)cyclohexyl)methyl)amino)butanoic    acid;-   (S)-4-amino-5-oxo-5-(((1-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) ethyl)cyclohexyl)methyl)amino)pentanoic    acid;-   (S)-2-amino-3-(1H-indol-3-yl)-N-((1-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)propanamide;-   (R)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)    butyl)butanamide;-   (R)—N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide;-   (R)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)    pyrrolidine-2-carboxamide;-   (R)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoro methoxy)benzo[d]    thiazol-2-yl)amino)ethyl) cyclohexyl)methyl)butanamide;-   (S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)-   methyl)pyrrolidine-2-carboxamide;-   (R)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)cyclohexyl)    methyl)pyrrolidine-2-carboxamide;-   4-amino-3,3-dimethyl-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)butanamide;-   (S)-3-(benzyloxy)-2-morpholino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-3-(benzyloxy)-2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-1-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   (R)-1-(1-(aminomethyl)cyclohexane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   N-methyl-2-(methylsulfonamido)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(tert-butoxy)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2 yl)amino)ethyl)acetamide;-   N,4,4-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) pentanamide;-   tert-Butyl (2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1-(trifluoromethyl)cyclopropyl)carbamate;-   N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((1-(trifluoromethyl)cyclopropyl)amino)acetamide;-   N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)-2-((2,2,2-trifluoroethyl)amino)acetamide    hydrochloride;-   2-acetamido-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl) acetamide;-   N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propionamide;-   N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)butyramide;-   N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)isobutyramide;-   N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)benzamide;-   2,2,2-trifluoro-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl) amino)-2-oxoethyl)acetamide;-   N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)    acetamide;-   2-(2-oxopiperazin-1-yl)-N-(6-(trifluoromethoxy)benzo    [d]thiazol-2-yl)acetamide;-   (S)—N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) piperazine-2-carboxamide;-   (R)—N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) piperazine-2-carboxamide;-   Benzyl    (2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate;-   2-aminoethyl (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate;-   Benzyl    ethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)    ethyl)carbamate;-   2-(Ethylamino)ethyl    (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate;-   Benzyl    methyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)    ethyl)carbamate;-   2-(Methylamino)ethyl    (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate;-   Benzyl    isopropyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate;-   2-(Isopropylamino)ethyl (6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)carbamate;-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    (5-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate;-   4-amino-2,2-dimethyl-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)butanamide;-   (S)-2-amino-N1,N5-bis(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pentanediamide;-   2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide;-   and 1,3-bis(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)urea.

Exemplary embodiments include compounds having the formula (I) through(XVI) or a pharmaceutically acceptable salt form thereof, in combinationwith an anticancer agent. Exemplary embodiments of anticancer agentsinclude but are not limited to Vemurafenib, Ipilimumab, Masitinib,Sorafenib, Lenalidomide, Oblimersen, Trametinib, Dabrafenib, RO5185426,Veliparib, Bosentan, YMI55, CNTO 95, CR011-vcMMAE, CY503, Lenvatinib,Avastin, Tasidotin, Ramucirumab, IPI-504, Tasisulam, KW2871, MPC-6827,RAF265, Dovitinib, Everolimus, MEK162, BKM120, Nilotinib, Reolysin,825A, Tremelimumab, PI-88, Elesclomol, STA9090, and Allovectin-7.

For the purposes of the present invention, a compound depicted by theracemic formula will stand equally well for either of the twoenantiomers or mixtures thereof, or in the case where a second chiralcenter is present, all diastereomers.

For the purposes of the present invention, a compound depicted by theracemic formula will stand equally well for either of the twoenantiomers or mixtures thereof, or in the case where a second chiralcenter is present, all diastereomers.

In all of the embodiments provided herein, examples of suitable optionalsubstituents are not intended to limit the scope of the claimedinvention. The compounds of the invention may contain any of thesubstituents, or combinations of substituents, provided herein.

Process

Compounds of the present teachings can be prepared in accordance withthe procedures outlined herein, from commercially available startingmaterials, compounds known in the literature, or readily preparedintermediates, by employing standard synthetic methods and proceduresknown to those skilled in the art. Standard synthetic methods andprocedures for the preparation of organic molecules and functional grouptransformations and manipulations can be readily obtained from therelevant scientific literature or from standard textbooks in the field.It will be appreciated that where typical or preferred processconditions (i.e. reaction temperatures, times, mole ratios of reactants,solvents, pressures, etc.) are given, other process conditions can alsobe used unless otherwise stated. Optimum reaction conditions can varywith the particular reactants or solvent used, but such conditions canbe determined by one skilled in the art by routine optimizationprocedures. Those skilled in the art of organic synthesis will recognizethat the nature and order of the synthetic steps presented can be variedfor the purpose of optimizing the formation of the compounds describedherein.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), mass spectrometry, or by chromatography such as highpressure liquid chromatography (HPLC), gas chromatography (GC),gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve protection and deprotection ofvarious chemical groups. The need for protection and deprotection andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene et al., Protective Groups in OrganicSynthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of whichis incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out insuitable solvents which can be readily selected by one skilled in theart of organic synthesis. Suitable solvents typically are substantiallynonreactive with the reactants, intermediates, and/or products at thetemperatures at which the reactions are carried out, i.e., temperaturesthat can range from the solvent's freezing temperature to the solvent'sboiling temperature. A given reaction can be carried out in one solventor a mixture of more than one solvent. Depending on the particularreaction step, suitable solvents for a particular reaction step can beselected.

The compounds of these teachings can be prepared by methods known in theart of organic chemistry. The reagents used in the preparation of thecompounds of these teachings can be either commercially obtained or canbe prepared by standard procedures described in the literature. Forexample, compounds of the present invention can be prepared according tothe method illustrated in the General Synthetic Schemes:

General Synthetic Schemes for Preparation of Compounds

The reagents used in the preparation of the compounds of this inventioncan be either commercially obtained or can be prepared by standardprocedures described in the literature. In accordance with thisinvention, compounds in the genus may be produced by one of thefollowing reaction schemes.

Compounds of formula (I) may be prepared according to the processoutlined in schemes 1-21.

Riluzole (1), a known compound, is reacted with a compound of theformula (2), a known compound or a compound made by known methods, inthe presence of a coupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (3). Acompound of the formula (3) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (4).

A compound of the formula (4) is reacted with a compound of the formula(5), a known compound or a compound made by known methods, in thepresence of a coupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (6). Acompound of the formula (6) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (7).

A compound of the formula (4) is reacted with a compound of (8), a knowncompound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (9).

A compound of the formula (4) is reacted with a compound of (10), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (11). Acompound of the formula (11) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (12).

A compound of the formula (4) is reacted with a compound of (13), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (14).

A compound of the formula (4) is reacted with a compound of (15), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (16). Acompound of the formula (16) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (17).

Riluzole (1), a known compound, is reacted with a compound of theformula (18), a known compound or a compound made by known methods, inthe presence of a coupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (19). Acompound of the formula (19) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (20).

A compound of the formula (20) is reacted with a compound of (21), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (22).

A compound of the formula (20) is reacted with a compound of (23), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (24). Acompound of the formula (24) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (25).

A compound of the formula (20) is reacted with a compound of (26), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (27).

A compound of the formula (20) is reacted with a compound of (28), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (29). Acompound of the formula (29) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (30).

A compound of the formula (20) is reacted with a compound of (31), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (32). Acompound of the formula (32) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (33).

A compound of the formula (20) is reacted with a compound of (34), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (35). Acompound of the formula (35) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (36).

A compound of the formula (20) is reacted with a compound of (37), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (38). Acompound of the formula (38) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (39).

A compound of the formula (25) is reacted with a compound of (40), aknown compound or a compound made by known methods, in the presence of abase such as triethylamine, diisopropylethylamine, N-methylmorpholineand the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, methylene chloride and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (41).

A compound of the formula (42), a known compound or a compounds preparedby known methods, is reacted with triphosgene in the presence of asolvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran,methylene chloride, chloroform, and the like. The resulting product isthen reacted with a compound of the formula (1) in the presence of abase such as triethylamine, diisopropylethylamine, N-methylmorpholineand the like, in the presence of a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chlorideand the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (43). A compound of theformula (44) is reacted with hydrogen bromide in the presence of aceticacid, optionally in the presence of a solvent such asN,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chlorideand the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (44).

A compound of the formula (45), a known compound or a compounds preparedby known methods, is reacted with triphosgene in the presence of asolvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran,methylene chloride, chloroform, and the like to provide a compound ofthe formula (46). A compound of the formula (46) is reacted with acompound of the formula (I) in the presence of a base such astriethylamine, diisopropylethylamine, N-methylmorpholine, and the like,in the presence of a solvent such as N, N-dimethylformamide,1,4-dioxane, tetrahydrofuran, methylene chloride and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (43).

A compound of the formula (48), a known compound or a compounds preparedby known methods, is reacted with a compound of the formula (49), aknown compound or a compounds prepared using known methods, in thepresence of a solvent such as N, N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, methylene chloride and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (50).

A compound of the formula (51), a known compound or a compounds preparedby known methods, is reacted with a compound of the formula (52), aknown compound or a compounds prepared using known methods, in thepresence of a solvent such as N,N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, methylene chloride and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (53).

A compound of the formula (54), a known compound or a compounds preparedby known methods, is reacted with a compound of the formula (55), aknown compound or a compounds prepared using known methods, in thepresence of a base such as triethylamine, diisopropylethylamine,N-methylmorpholine and the like, in the presence of a solvent such asN,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chlorideand the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (56). A compound of theformula (56) is reacted with a compound of the formula (57), a knowncompound or a compounds prepared by known methods, in the presence of asolvent such as N,N-dimethylformamide, dimethylsulfoxide, 1,4-dioxane,tetrahydrofuran, methylene chloride and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (58).

A compound of the formula (56) is reacted with a compound of the formula(59), a known compound or a compounds prepared by known methods whereinM is a counter ion such as sodium, potassium, tetrabutyl ammonium, andthe like, in the presence of a solvent such as N,N-dimethylformamide,dimethylsulfoxide, 1,4-dioxane, tetrahydrofuran, methylene chloride andthe like, optionally with heating, optionally with microwave irradiationto provide a compound of the formula (60). A compound of the formula(60) is reacted with hydrogen in the presence of a catalyst such aspalladium on carbon, palladium on barium sulfate, palladium (II)acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran,1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane,N,N-dimethylformamide, and the like, to provide a compound of theformula (61). A compound of the formula (61) is reacted with a compoundof the formula (62), a known compound or a compound prepared by knownmethods, in the presence of a hydride source such as sodium borohydride,sodium cyanoborohydride, sodium triacetoxy borohydride, and the like,optionally in the presence of an acid such as acetic acid,trifluoroacetic acid, formic acid, and the like, in an organic solventsuch as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane,dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (63). A compound of theformula (63) is reacted with a compound of the formula (62), a knowncompound or a compound prepared by known methods, in the presence of ahydride source such as sodium borohydride, sodium cyanoborohydride,sodium triacetoxy borohydride, and the like, optionally in the presenceof an acid such as acetic acid, trifluoroacetic acid, formic acid, andthe like, in an organic solvent such as methanol, ethanol, ethylacetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform,1,2-dichloroethane, N,N-dimethylformamide, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (64).

Schemes 1-21 describe the preparation of compounds containing chiralcenters. Those skilled in the art of organic synthesis will recognizethat the chemistry described in schemes 1-21 can be applied to preparethe enantiomer of the compounds described employing starting materialcontaining the opposite stereochemistry. In the case of compounds withmultiple chiral centers those skilled in the art of organic synthesiswill recognize that the chemistry described in schemes 1-21 can beemployed to prepare compounds of the disclosure from starting materialscontaining the desired chirality and each chiral center.

EXAMPLES

Example 1-267 provides methods for preparing representative compounds offormula (1). The skilled practitioner will know how to substitute theappropriate reagents, starting materials and purification methods knownto those skilled in the art, in order to prepare additional compounds ofthe present invention.

The following procedures were employed to purify and analyze compoundsof the disclosure. Those skilled in the art would understand thatalternate methods could be employed to analyze and purify the compoundsof the disclosure.

Method A: LC/MS data were determined with a Waters Alliance 2695 HPLC/MS(Waters Symmetry C18, 4.6×75 mm, 3.5 μm) with a 2996 diode arraydetector from 210-400 nm; the solvent system is 5-95% acetonitrile inwater (with 0.1% TFA) over nine minutes using a linear gradient, andretention times are in minutes. Mass spectrometry was performed on aWaters ZQ using electrospray in positive mode.

Method B: Preparative reversed phase HPLC was performed on a WatersSunfire column (19×50 mm, C18, 5 μm) with a 10 min mobile phase gradientof 10% acetonitrile/water to 90% acetonitrile/water with 0.1% TFA asbuffer using 214 and 254 nm as detection wavelengths. Injection andfraction collection were performed with a Gilson 215 liquid handlingapparatus using Trilution LC software.

Method C: LC/MS data were determined on a Shimadzu LC 20AD instrumentwith a Phenomenex Luna C18 (3 μm) 50×3.0 mm column. Mobile phaseconsisted of water and acetonitrile with 0.1% formic acid buffer.Gradient was 10-90% acetonitrile over three minutes and held at 90%acetonitrile for two minutes. Detection was performed on diode arraydetector from 210-400 nm and retention times are in minutes. Massspectra were determined on an Applied Biosystems MDS Sciex API 2000instrument using electrospray ionization.

Example 1: Synthesis of2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide

To a solution of 2-amino-6-(trifluoromethoxy)benzimidazole (0.50 g, 2.1mmol), N-(t-butyloxycarbonyl) glycine (0.56 g, 3.2 mmol) andN,N-diisopropylethylamine (0.41 g, 3.2 mmol, 0.57 ml) indimethylformamide (7 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 1.2 g, 3.2 mmol) and the mixturestirred at 20° C. for 18 hours. Ethyl acetate (100 ml) was added and themixture was washed with water (2×75 ml), 1N HCl (75 ml), water (75 ml),1M sodium carbonate solution (75 ml) and brine. The organic layer wasdried over sodium sulfate and evaporated. The residue waschromatographed on silica gel eluted with a gradient of ethyl acetate inhexanes (50% to 75%) to leave the product as a white foamy solid (0.78g, 95%). LC/MS method A: R_(t)=5.92 min., (M+H)⁺=392. The product wasdissolved in 4N HCl/1,4-dioxane and stirred for 2 h. The solvents wereevaporated in an HCl compatible Genevac evaporator to leave a whitesolid mono HCl product (0.69 g, 100%, 95% overall yield). LC/MS methodA: R_(t)=3.53 min., (M+H)⁺=292.

Example 2: Synthesis of2-(Methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) acetamidehydrochloride

2-(Methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) acetamidehydrochloride was prepared according to the procedure of example 1 from2-amino-6-(trifluoromethoxy) benzimidazole (0.50 g, 2.1 mmol) andN-(t-butyloxycarbonyl)sarcosine (0.60 g, 3.2 mmol). Yield forintermediate=0.96 g (100%). LC/MS method A: R_(t)=5.92 min., (M+H)⁺=406.Yield for final product (0.82 g, 100%, 100% overall). LC/MS method A:R_(t)=3.60 min., (M+H)⁺=306.

Example 3: Synthesis of2-(Ethylamino)-N-(6-(trifluoromethoxy)benzo[d]triazol-2-yl)acetamidehydrochloride

2-(Ethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride was prepared according to the procedure of example 1 from2-amino-6-(trifluoromethoxy)benzimidazole (117 mg, 0.5 mmol) andN-t-butyloxycarbonyl-2-(ethylamino)acetic acid (122 mg, 0.6 mmol). Yieldfor Boc protected intermediate 182 mg (87%). LC/MS method A: R_(t)=6.20min., (M+H)⁺=420. Yield for final product (142 mg, 87% overall). LC/MSmethod A: R_(t)=3.67 min., (M+H)⁺=320.

Example 4: Synthesis of2-(Isopropylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride

2-(Isopropylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride was prepared according to the procedure of example 1 from2-amino-6-(trifluoromethoxy) benzimidazole (117 mg, 0.5 mmol) andN-t-butyloxycarbonyl-2-(isopropylamino)acetic acid (131 mg, 0.6 mmol).Yield for Boc protected intermediate 146 mg (67%). LC/MS method A:R_(t)=6.39 min., (M+H)⁺=434. Yield for final product (110 mg, 67%overall). LC/MS method A: R_(t)=3.76 min., (M+H)⁺=334.

Example 5: Synthesis of(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

To a solution of 2-amino-6-(trifluoromethoxy)benzimidazole (50 mg, 0.21mmol), N-t-butyloxycarbonyl-L-proline (69 mg, 0.32 mmol),1-Hydroxy-7-azabenzotriazole (42 mg, 0.32 mmol) andN,N-diisopropylethylamine (41 mg, 0.32 mmol, 57 μl) in N,N-dimethylformamide (0.35 ml) was added 2-chloro-1-methylpyridinium iodide (82 mg,0.32 mmol) and the yellow solution stirred for 72 hours. Water (0.25 ml)and methanol (1 ml) were added and the mixture was purified by reversephase HPLC (method B). The product fractions were combined and thesolvents were removed on a Genevac evaporator. This left 59 mg (59%) offoamy solid. LC/MS method A: R_(t)=6.21 min., (M+H)⁺=432. The productwas dissolved in 4N HCl/1,4-dioxane and stirred for 2 h. The solventswere evaporated in an HCl compatible Genevac evaporator to leave a whitesolid mono HCl product (45 mg, 100%, 59% overall yield). LC/MS method A:R_(t)=3.72 min. (M+H)⁺=332.

Example 6: Synthesis of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 5 from2-amino-6-(trifluoromethoxy) benzimidazole (50 mg, 0.21 mmol) andN-t-butyloxycarbonyl-D-proline (69 mg, 0.32 mmol). Yield for Bocprotected intermediate 64 mg (71%). LC/MS method A: R_(t)=6.21 min.,(M+H)⁺=432. Yield for final product (46 mg, 60% overall). LC/MS methodA: R_(t)=3.72 min., (M+H)⁺=332.

Example 7: Synthesis of(R)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)propanamide

(R)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide was prepared according to the procedure of example 5 from2-amino-6-(trifluoromethoxy) benzimidazole (100 mg, 0.42 mmol) andN-t-butyloxycarbonyl-D-phenylalanine (170 mg, 0.64 mmol). Yield for Bocprotected intermediate 91 mg (44%). LC/MS method A: R_(t)=6.67 min.,(M+H)⁺=482. Yield for final product (70 mg, 89%, 39% overall). LC/MSmethod A: R_(t)=3.99 min., (M+H)⁺=382.

Example 8: Synthesis of(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)propanamide hydrochloride

(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide hydrochloride was prepared according to the procedure ofexample 5 from 2-amino-6-(trifluoro methoxy)benzimidazole (100 mg, 0.42mmol) and N-t-butyloxycarbonyl-L-phenylalanine (170 mg, 0.64 mmol).Yield for Boc protected intermediate 70 mg (34%). LC/MS method A:R_(t)=6.66 min., (M+H)⁺=482. Yield for final product (50 mg, 82%, 28%overall). LC/MS method A: R_(t)=3.99 min., (M+H)⁺=382.

Example 9: Synthesis of(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamidewas prepared according to the procedure of example 5 from2-amino-6-(trifluoromethoxy) benzimidazole (0.50 g, 2.1 mmol) andN-t-butyloxycarbonyl-L-azetidine-2-carboxylic acid (0.64 g, 3.2 mmol).Yield for Boc protected intermediate 0.62 g (71%). LC/MS method A:R_(t)=6.13 min., purity >95%, (M+H)⁺=418. Yield for final product (0.52g, 100%, 71% overall). LC/MS method A: R_(t)=3.66 min., purity >90%,(M+H)⁺=318.

Example 10: Synthesis of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamidewas prepared according to the procedure of example 5 from2-amino-6-(trifluoromethoxy) benzimidazole (0.50 g, 2.1 mmol) andN-t-butyloxycarbonyl-D-azetidine-2-carboxylic acid (0.64 g, 3.2 mmol).Yield for Boc protected intermediate 0.60 g (69%). LC/MS method A:R_(t)=6.13 min., (M+H)⁺=418. Yield for final product (0.51 g, 100%, 69%overall). LC/MS method A: R_(t)=3.66 min., (M+H)⁺=318.

Example 11: Synthesis of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide

(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 5 from2-amino-6-(trifluoromethoxy) benzimidazole (234 mg, 1.0 mmol) and(R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (300 mg, 1.3mmol). Yield for Boc protected intermediate 78 mg (17%). LC/MS method A:R_(t)=6.72 min., (M+H)⁺=446. Yield for final product (61 mg, 100%, 17%overall). LC/MS method A: R_(t)=3.78 min. (M+H)⁺=346.

Example 12: Synthesis of(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide

(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 5 from2-amino-6-(trifluoromethoxy)benzimidazole (234 mg, 1.0 mmol) and(S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (300 mg, 1.3mmol). Yield for Boc protected intermediate 78 mg (17%). LC/MS method A:R_(t)=6.72 min., (M+H)⁺=446. Yield for final product (61 mg, 100%, 17%overall). LC/MS method A: R_(t)=3.78 min., (M+H)⁺=346.

Example 13: Synthesis of2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide was prepared according to the procedure ofexample 1 from 2-amino-6-(trifluoromethoxy) benzimidazole (234 mg, 1.0mmol) and N-t-butyloxycarbonyl-2-amino-2-methylpropanamide (305 mg, 1.5mmol). Yield for Boc protected intermediate 280 mg (67%). LC/MS methodA: R_(t)=6.22 min., (M+H)⁺=420. Yield for final product (205 mg, 100%,67% overall). LC/MS method A: R_(t)=3.68 min., (M+H)⁺=320.

Example 14: Synthesis of1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide

1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamidewas prepared according to the procedure of example 1 from2-amino-6-(trifluoromethoxy) benzimidazole (234 mg, 1.0 mmol) andN-t-butyloxycarbonyl-1-aminocyclopropanecarboxylic acid (261 mg, 1.3mmol). Yield for Boc protected intermediate 281 mg (67%). LC/MS methodA: R_(t)=6.08 min., (M+H)⁺=418. Yield for final product (227 mg, 100%,67% overall). LC/MS method A: R_(t)=3.65 min., (M+H)⁺=318.

Example 15: Synthesis of1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamide

1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidewas prepared according to the procedure of example 1 from2-amino-6-(trifluoromethoxy) benzimidazole (234 mg, 1.0 mmol) andN-t-butyloxycarbonyl-1-aminocyclobutanecarboxylic acid (280 mg, 1.3mmol). Yield for Boc protected intermediate 281 mg (65%). LC/MS methodA: R_(t)=6.34 min., (M+H)⁺=432. Yield for final product (248 mg, 100%,65% overall). LC/MS method A: R_(t)=3.75 min., (M+H)⁺=332.

Example 16: Synthesis of2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

To a solution of 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (0.40g, 1.2 mmol), N-(t-butyloxycarbonyl)sarcosine (0.28 g, 1.5 mmol) andN,N-diisopropylethylamine (0.39 g, 3.0 mmol, 0.54 ml) inN,N-dimethylformamide (10 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 0.57 g, 1.5 mmol) and the reactionmixture stirred for 18 hours. Ethyl acetate (100 ml) was added and themixture was washed with water (2×50 ml), 1N HCl (50 ml), saturatedsodium bicarbonate solution (50 ml) and brine (25 ml). The organicsolution was dried over sodium sulfate and evaporated to a light yellowfoamy solid which was dissolved in 4N HCl in 1,4-dioxane. The mixturestirred 2 hours and the white precipitate was filtered on a glass frit(medium), washed with 1,4-dioxane and ether and dried under vacuum toleave 344 mg (76%) of white crystalline product. LC/MS method A:R_(t)=3.62 min., (M+H)⁺=363.

Example 17: Synthesis of(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide

(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamidewas prepared according to the procedures of example 16 from2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (60 mg, 0.25 mmol) and N-(t-butyloxycarbonyl)proline (89mg, 0.32 mmol). Yield for Boc protected intermediate 62 mg (51%). LC/MSmethod A: R_(t)=6.34 min., (M+H)⁺=432. Yield for final product (64 mg,100%, 51% overall). LC/MS method A: R_(t)=3.74 min., (M+H)⁺=389.

Example 18: Synthesis of(R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

A solution of 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol), N-(1-butyloxycarbonyl)-D-alanine (15 mg, 79 mmol) andN,N-Diisopropylethylamine (20 mg, 0.16 mmol, 28 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (30 mg, 79 μmol) and shaken for 18 hours. Theproduct was isolated following direct injection reverse phase HPLC(method B) and evaporation of the product fractions on a Genevacevaporator. The product weighed 23 mg (82%). The compound was dissolvedin 4N HCl/1,4-dioxane, shaken 2 hours then evaporated on a Genevacevaporator to leave the product as a white solid (20 mg, 82%) mono HClsalt. LC/MS method A: R_(t)=3.59 min., (M+H)⁺=363.

The following compounds were prepared using the same method and scale asexample 18.

Example 19: Synthesis of3-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

3-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamidewas prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-β-alanine (15 mg, 79 μmol). Yield=5.5 mg (23%).LC/MS method A: R_(t)=3.57 min., (M+H)⁺=363.

Example 20: Synthesis of1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopropane-1-carboxamide

1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopropane-1-carboxamide was prepared according to the procedure of example18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-1-(t-butyloxycarbonyl)aminocyclopropane-1-carboxylic acid (16 mg, 79μmol). Yield=20 mg (80%). LC/MS method A: R_(t)=3.60 min., (M+H)⁺=375.

Example 21: Synthesis of(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)azetidine-2-carboxamide

(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)azetidine-2-carboxamidewas prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(S)—N-(t-butyloxycarbonyl)azctidine-2-carboxylic acid (16 mg, 79 μmol).Yield=20 mg (80%). LC/MS method A: R_(t)=3.62 min., (M+H)⁺=375.

Example 22: Synthesis of2-amino-2-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

2-amino-2-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)aminoisobutyric acid (16 mg, 79 μmol). Yield=20 mg(80%). LC/MS method A: R_(t)=3.63 min., (M+H)⁺=377.

Example 23: Synthesis of(S)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(S)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-N-methyl-L-alanine (16 mg, 79 μmol). Yield=20 mg(80%). LC/MS method A: R_(t)=3.64 min., (M+H)⁺=377.

Example 24: Synthesis of(R)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(R)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-N-methyl-D-alanine (16 mg, 79 μmol). Yield=18 mg(72%). LC/MS method A: R_(t)=3.64 min., (M+H)⁺=377.

Example 25: Synthesis of(R)-2-amino-3-hydroxy-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(R)-2-amino-3-hydroxy-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 18from 2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-D-serine (16 mg, 79 μmol). Yield=16 mg (63%).LC/MS method A: R_(t)=3.50 min., (M+H)⁺=379.

Example 26: Synthesis of(R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pent-4-ynamide

(R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino)ethyl)pent-4-ynamide was prepared according to theprocedure of example 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and N-(1-butyloxycarbonyl)-(R)-2-amino-4-pentynyl carboxylic acid(17 mg, 79 μmol). Yield=22 mg (85%). LC/MS method A: R_(t)=3.71 min.,(M+H)⁺=387.

Example 27: Synthesis of (S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pent-4-ynamide

(S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pent-4-ynamide was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(Q-butyloxycarbonyl)-(S)-2-amino-4-pentynyl carboxylic acid (17 mg, 79μmol). Yield=22 mg (85%). LC/MS method A: R_(t)=3.71 min., (M+H)⁺=387.

Example 28: Synthesis of (R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide

(R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide was preparedaccording to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-D-proline (17 mg, 79 μmol). Yield=21 mg (81%).LC/MS method A: R_(t)=3.70 min., (M+H)⁺=389.

Example 29: Synthesis of 1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclobutane-1-carboxamide

1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclobutane-1-carboxamide was preparedaccording to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and1-(N-(t-butyloxycarbonyl)amino) cyclobutanecarboxylic acid (17 mg, 79μmol). Yield=1.5 mg (5.8%). LC/MS nmethod A: R_(t)=3.69 min.,(M+H)⁺=389.

Example 30: Synthesis of (S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanamide

(S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl) pentanamide was prepared according tothe procedure of example 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and (S)-2-(N-(t-butyloxycarbonyl)amino)pentanoic acid (17 mg, 79μmol). Yield=19 mg (73%). LC/MS method A: R_(t)=3.88 min., (M+H)⁺=391.

Example 31: Synthesis of (R)-2-amino-3-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide

(R)-2-amino-3-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide was prepared according to the procedure of example 18from 2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(R)-2-(N-(t-butyloxycarbonyl)valine (17 mg, 79 μmol). Yield=21 mg (81%).LC/MS method A: R_(t)=3.83 min., (M+H)⁺=391.

Example 32: Synthesis of(S)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide

(S)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl) pyrrolidine-2-carboxamide was preparedaccording to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(S)—N-t-butyloxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (18 mg, 79μmol). Yield=16 mg (60%). LC/MS method A: R_(t)=3.64 min., (M+H)⁺=403.

Example 33: (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide

(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(S)—N-t-butyloxycarbonylpiperidine-2-carboxylic acid (18 mg, 79 μmol).Yield=20 mg (75%). LC/MS method A: R_(t)=3.73 min., (M+H)⁺=403.

Example 34: Synthesis of (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide

(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μol) and(S)—N-t-butyloxycarbonylmorpholine-2-carboxylic acid (18 mg, 79 μmol).Yield=24 mg (89%). LC/MS method A: R_(t)=3.64 min., (M+H)⁺=405.

Example 35: Synthesis of (R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide

(R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(R)—N-t-butyloxycarbonylmorpholine-2-carboxylic acid (18 mg, 79 μmol).Yield=25 mg (93%). LC/MS method A: R=3.64 min., (M+H)⁺=405.

Example 36: Synthesis of (R)-2-amino-4-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanamide

(R)-2-amino-4-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanamide was prepared according to the procedure of example 18from 2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-t-butyloxycarbonyl-D-leucine (18 mg, 79 μmol). Yield=21 mg (78%).LC/MS method A: R_(t)=4.01 min., (M+H)⁺=405.

Example 37: Synthesis of(R)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide

(R)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide was preparedaccording to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(R)—N-t-butyloxycarbonyl-4-oxopiperidine-2-carboxylic acid (19 mg, 79μmol). Yield=15 mg (54%). LC/MS method A: R_(t)=3.68 min., (M+H)⁺=417.

Example 38: Synthesis of4-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)tetrahydro-2H-pyran-4-carboxamide

4-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)tetrahydro-2H-pyran-4-carboxamide was preparedaccording to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and4-N-t-butyloxycarbonylamino-2,3,5,6-tetrahydropyran-4H-4-carboxylic acid(19 mg, 79 μmol). Yield=24 mg (87%). LC/MS method A: R_(t)=3.63 min.,(M+H)⁺=419.

Example 39: (R)-2-amino-N1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanediamide

(R)-2-amino-N1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl) pentanediamide: was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-t-butyloxycarbonyl-D-glutamine (20 mg, 79 μmol). Yield=24 mg (72%).LC/MS method A: R_(t)=3.47 min., (M+H)⁺=420.

Example 40: (R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-3-phenylpropanamide

(R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-3-phenylpropanamide was preparedaccording to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-t-butyloxycarbonyl-D-phenylalanine (21 mg, 79 μmol). Yield=22 mg(76%). LC/MS method A: R_(t)=4.11 min., (M+H)⁺=439.

Example 41:(R)-2-amino-3-cyclohexyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(R)-2-amino-3-cyclohexyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 18from 2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-t-butyloxycarbonyl-D-cyclohexylalanine (21 mg, 79 μmol). Yield=15 mg(51%). LC/MS method A: R_(t)=4.43 min., (M+H)⁺=445.

Example 42: Synthesis of(R)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(R)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure ofexample 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and N-t-butyloxycarbonyl-O-benzyl-D-serine (23 mg, 79 μmol).Yield=25 mg (81%). LC/MS method A: R_(t)=4.30 min., (M+H)⁺=469.

Example 43: Synthesis of(S)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(S)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure ofexample 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and N-t-butyloxycarbonyl-O-benzyl-L-serine (23 mg, 79 μmol).Yield=26 mg (84%). LC/MS method A: R_(t)=4.30 min., (M+H)⁺=469.

Example 44: Synthesis of(R)-2-amino-3-(1H-indol-3-yl)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(R)-2-amino-3-(1H-indol-3-yl)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamidewas prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-t-butyloxycarbonyl-L-tryptophan (24 mg, 79 μmol). Yield=22 mg (70%).

Example 45: Synthesis of (2S,4R)-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide

(2S,4R)-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide was prepared according to the procedureof example 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and tert-butyl(2S,4R)-4-(benzyloxy)-2-carbamoylpyrrolidine-1-carboxylate (25 mg, 79μmol). Yield=24 mg (74%). LC/MS method A: R_(t)=4.13 min., (M+H)⁺=495.

Example 46: Synthesis of (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide

(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(S)—N,N′-di-(tert-butyloxycarbonyl) morpholine-2-carboxylic acid (26 mg,79 μmol). Yield=23 mg (70%). LC/MS method A: R_(t)=3.23 min.,(M+H)⁺=404.

Example 47: Synthesis of(R)-2-amino-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide

(R)-2-amino-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide was prepared according to the procedure ofexample 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and N-t-butyloxycarbonyl-O-benzyl-D-homoserine (27 mg, 79 μmol).Yield=26 mg (77%). LC/MS method A: R_(t)=4.39 min (M+H)⁺=482.

Example 48: Synthesis of(R)-1-(N,N-dimethyl-L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

A solution of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidefrom example 6 above (0.11 g, 0.30 mmol), N,N-dimethyl-L-valine (52 mg,0.36 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol, 65 μl) inN,N-dimethylformamide (2 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (137 mg, 0.36 mmol) and stirred 72 hours. Theproduct was purified by reverse phase HPLC (method B, direct injectionof the reaction mixture). The product fractions were combined andevaporated on a Genevac evaporator to leave the mono TFA salt product asa white powder (31 mg, 18%). LC/MS method A: R_(t)=4.06 min.,(M+H)⁺=459.

Example 49: Synthesis of(R)-1-(L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

A solution of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidefrom example 6 above (25 mg, 0.68 μmol), N-t-butyloxycarbonyl-L-valine(18 mg, 81 μmol) and N,N-diisopropylethylamine (10 μmol, 18 μl) inN,N-dimethylformamide (0.3 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (39 mg, 10 μmol) and stirred 72 hours. Theproduct was purified by reverse phase HPLC (method B, direct injectionof the reaction mixture). The product fractions were combined andevaporated on a Genevac evaporator to leave the product as a whitepowder which was stirred for 2 hours in 4N HCl/1,4-dioxane (2 ml). Thesolvents were evaporated to leave the product as a white solid (27 mg,85% two steps). LC/MS method A: R_(t)=4.23 min., (M+H)⁺=431.02.

Example 50: Synthesis of(R)-1-D-valyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-D-valyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according to the procedure ofexample 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-t-butyloxycarbonyl-D-valine (26 mg, 0.13 mmol).Yield=35 mg, 75% two steps. LC/MS method A: R_(t)=4.24 min.,(M+H)⁺=431.02.

Example 51: Synthesis of(R)-1-glycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-glycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according to the procedure ofexample 49 from (R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 mmol) andN-t-butyloxycarbonylglycine (25 mg, 0.13 mmol). Yield=42 mg, 100% twosteps. LC/MS method A: R_(t)=3.78 min., (M+H)⁺=388.94.

Example 52: (R)-1-N-ethylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) pyrrolidine-2-carboxamide

(R)-1-N-ethylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (74 mg, 0.2 mmol) and N-Boc-N-ethyl glycine(61 mg, 0.30 mmol) Yield=88 mg, 97% two steps. LC/MS method A:R_(t)=3.94 min., (M+H)⁺=417.02.

Example 53: Synthesis of(R)-1-N-isopropylglycinyl-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-N-isopropylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2carboxamide was prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (74 mg, 0.2 mmol) andN-t-butyloxycarbonyl-N-isopropyl glycine (65 mg, 0.30 mmol). Yield=98mg, 100% two steps. LC/MS method A: R_(t)=4.03 min., (M+H)⁺=431.09.

Example 54: Synthesis of (R)-1-N-t-butylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-N-t-butylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according tothe procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(74 mg, 0.2 mmol) and N-t-butyloxycarbonyl-N-terbutyl glycine (69 mg,0.30 mmol). Yield=86 mg, 89% two steps. LC/MS method A: R_(t)=4.13 min.,(M+H)⁺=445.10.

Example 55: Synthesis of(R)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 mmol) andN-t-butyloxycarbonyl-3-amino-2,2-dimethylpropanoic acid (29 mg, 0.13mmol). Yield=53 mg, 100% two steps. LC/MS method A: R_(t)=4.01 min.,(M+H)⁺=431.02.

Example 56: Synthesis of(R)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according to theprocedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(74 mg, 0.2 mmol) and N-t-butyloxycarbonyl-1-(aminomethyl)cyclopropanecarboxylic acid (56 mg, 0.26 mmol). Yield=93 mg, 100% two steps. LC/MSmethod A: R_(t)=3.92 min., (M+H)⁺=429.05.

Example 57: Synthesis of(R)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according to theprocedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(74 mg, 0.2 mmol) and N-t-butyloxycarbonyl-1-(aminomethyl)cyclopentanecarboxylic acid (63 mg, 0.26 mmol). Yield=91 mg, 92% two steps. LC/MSmethod A: R_(t)=4.21 min., (M+H)⁺=457.13.

Example 58: Synthesis of(R)-1-(1-(aminomethyl)cyclohexane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-(1-(aminomethyl)cyclohexane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-t-butyloxycarbonyl-1-(aminomethyl)cyclohexanecarboxylic acid (33 mg, 0.13 mmol). Yield=28 mg, 55% two steps. LC/MSmethod A: R_(t)=4.54 min., (M+H)⁺=471.08.

Example 59: Synthesis of(S)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according to the procedure ofexample 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-t-butyloxycarbonyl-2-amino-2,2-dimethylpropanecarboxylic acid (29 mg, 0.13 mmol). Yield=45 mg, 96% two steps. LC/MSmethod A: R_(t)=4.03 min., (M+H)⁺=431.02.

Example 60: Synthesis of(S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according to theprocedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 μmol) and N-t-butyloxycarbonyl-1-(aminomethyl)cyclopropanecarboxylic acid (29 mg, 0.13 μmol). Yield=42 mg, 90% two steps. LC/MSmethod A: R_(t)=3.94 min., (M+H)⁺=428.98.

Example 61: Synthesis of(S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 μmol) and N-t-butyloxycarbonyl-1-(aminomethyl)cyclopentanecarboxylic acid (29 mg, 0.13 μmol). Yield=33 mg, 67% two steps. LC/MSmethod A: R_(t)=4.21 min., (M+H)⁺=457.07.

Example 62:(S)-1-(D-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(D-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (25 mg, 68 μmol) andN-t-butyloxycarbonyl-D-valine (18 mg, 82 μmol). Yield=33 mg (48%, twosteps). LC/MS method A: R_(t)=4.23 min., (M+H)⁺=431.13.

Example 63: Synthesis of(S)-1-(L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 μmol) andN-(t-butyloxycarbonyl)valine (24 mg, 0.12 μmol). Yield=35 mg (75%, twosteps). LC/MS method A: R_(t)=4.23 min., (M+H)⁺=431.02.

Example 64: Synthesis of(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 μmol) and N-(t-butyloxycarbonyl)glycine (21 mg, 0.12 μmol).Yield=45 mg (100%, two steps). LC/MS method A: R_(t)=3.78 min.,(M+H)⁺=388.94.

Example 65: Synthesis of(S)-1-(D-alanyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(D-alanyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 μmol) andN-(t-butyloxycarbonyl)-D-alanine (23 mg, 0.12 μmol). Yield=55 mg (100%,two steps). LCMS method A: R_(t)=3.82 min., (M+H)⁺=403.01.

Example 66: Synthesis of(S)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-(t-butyloxycarbonyl)sarcosine (23 mg, 0.12mmol). Yield=31 mg (71%, two steps). LC/MS method A: R_(t)=3.85 min.,(M+H)⁺=403.01.

Example 67: Synthesis of(S)-1-(ethylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(ethylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-(t-butyloxycarbonyl)-N-ethylglycine (24 mg, 0.12mmol). Yield=35 mg (65%, two steps). LC/MS method A: R_(t)=3.94 min.,(M+H)⁺=416.95.

Example 68: Synthesis of(S)-1-(isopropylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(isopropylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-(t-butyloxycarbonyl)-N-isopropylglycine (26 mg,0.12 mmol). Yield=43 mg (79%, two steps). LC/MS method A: R_(t)=4.06min., (M+H)⁺=431.02.

Example 69: Synthesis of(S)-1-(tert-butylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(tert-butylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(65 mg, 0.18 mmol) and N-(t-butyloxycarbonyl)-N-t-butylglycine (61 mg,0.26 mmol). Yield=62 mg (73%, two steps). LC/MS method A: R_(t)=4.16min., (M+H)⁺=445.10.

Example 70: Synthesis of(S)-1-(D-leucyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(D-leucyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide: was prepared according to theprocedure of example 49 from (S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 mmol) andN-(t-butyloxycarbonyl)-D-leucine (26 mg, 0.12 mmol). Yield=33 mg (69%,two steps). LC/MS method A: R_(t)=4.18 min. (M+H)⁺=445.03.

Example 71: Synthesis of(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 mmol) andN-t-butyloxycarbonyl-beta-alanine (23 mg, 0.12 mmol). Yield=46 mg (100%,two steps). LC/MS method A: R_(t)=3.64 min., (M+H)⁺=403.01.

Example 72: Synthesis of(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)azetidine-2-carboxamide(37 mg, 0.1 mmol) and N-t-butyloxycarbonylglycine (26 mg, 0.13 mmol).Yield=21 mg (43%, two steps). LC/MS method A: R_(t)=3.69 min.,(M+H)⁺=374.94.

Example 73: Synthesis of(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide(37 mg, 0.1 mmol) and N-t-butyloxycarbonyl-beta-alanine (29 mg, 0.13mmol). Yield=18 mg (36%, two steps). LC/MS method A: R_(t)=3.76 min.,(M+H)⁺=388.94.

Example 74: Synthesis of(S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide was prepared according to theprocedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamideTFA salt (46 mg, 0.1 mmol) andN-t-butyloxycarbonyl-1-(aminomethyl)cyclopropane carboxylic acid (29 mg,0.13 mmol). Yield=49 mg (93%, two steps). LC/MS method A: R_(t)=3.90min., (M+H)⁺=414.98.

Example 75: Synthesis of(S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide was prepared according to theprocedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamideTFA salt (46 mg, 0.1 mmol) andN-t-butyloxycarbonyl-1-(aminomethyl)cyclopentane carboxylic acid (29 mg,0.13 mmol). Yield=49 mg (88%, two steps). LC/MS method A: R_(t)=4.16min., (M+H)⁺=443.06.

Example 76: Synthesis of(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide

(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclohexane-2-carboxamidehydrochloride (41 mg, 0.10 mmol) and N-t-butyloxycarbonylglycine (26 mg,0.13 mmol). Yield=43 mg (98%, two steps). LC/MS method A: R_(t)=4.08min., (M+H)⁺=402.94.

Example 77: Synthesis of(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide

(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclohexane-2-carboxamidehydrochloride (41 mg, 0.10 mmol) and N-t-butyloxycarbonyl-beta-alanine(29 mg, 0.13 mmol). Yield=42 mg (98%, two steps). LC/MS method A:R_(t)=4.15 min., (M+H)⁺=416.95.

Example 78: Synthesis of(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide

(R)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclohexane-2-carboxamidehydrochloride (30 mg, 0.073 mmol) and N-t-butyloxycarbonylglycine (17mg, 0.098 mmol). Yield=18 mg (55%, two steps). LCMS method A: R_(t)=4.17min., (M+H)⁺=402.94.

Example 79: Synthesis of(R)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide

(R)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclohexane-2-carboxamidehydrochloride (30 mg, 0.073 mmol) and N-t-butyloxycarbonylglycine (18mg, 0.098 mmol). Yield=28 mg (82%, two steps). LC/MS method A:R_(t)=4.25 min., (M+H)⁺=416.95.

Example 80: Synthesis of1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide

1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide hydrochloride (36 mg, 0.10 mmol)and N-t-butyloxycarbonylglycine (23 mg, 0.13 mmol). Yield=35 mg (85%,two steps). LC/MS method A: R_(t)=3.90 min., (M+H)⁺=375.01.

Example 81: Synthesis of1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide

1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamidehydrochloride (36 mg, 0.10 mmol) and N-t-butyloxycarbonyl-N-methylglycine (25 mg, 0.13 mmol). Yield=28 mg (66%, two steps). LC/MS methodA: R_(t)=3.94 min., (M+H)⁺=389.01.

Example 82: Synthesis of1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamide hydrochloride (33 mg, 0.10 mmol) andN-t-butyloxycarbonylglycine (23 mg, 0.13 mmol). Yield=36 mg (85%, twosteps). LC/MS method A: R_(t)=4.06 min., (M+H)⁺=388.94.

Example 83: Synthesis of1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide was prepared according to theprocedure of example 49 from 1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamide hydrochloride (33 mg, 0.10 mmol) andN-t-butyloxycarbonyl-N-methylglycine (25 mg, 0.13 mmol). Yield=22 mg(50%, two steps). LC/MS method A: R_(t)=4.13 min., (M+H)⁺=403.01.

Example 84: Synthesis of1-(3-amino-22-dimethylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanccarboxamidehydrochloride (37 mg, 0.10 mmol) andN-t-butyloxycarbonyl-2,2-dimethyl-beta-alanine (30 mg, 0.15 mmol).Yield=30 mg (55%, two steps). LC/MS method A: R_(t)=4.20 min.,(M+H)⁺=431.16.

Example 85: Synthesis of1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)cyclopentane-1-carboxamide

1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)cyclopentane-1-carboxamide was prepared according to the procedure ofexample 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidehydrochloride (37 mg, 0.10 mmol) andN-t-butyloxycarbonyl-1-(aminomethyl)cyclopentane carboxylic acid (33 mg,0.15 mmol). Yield=23 mg (47%, two steps). LC/MS method A: R_(t)=4.40min., (M+H)⁺=457.13.

Example 86: Synthesis of1-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide was prepared according to the procedure of example49 from 1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamide hydrochloride (37 mg, 0.10 mmol)and N-t-butyloxycarbonyl-N-isopropylglycine (30 mg, 0.15 mmol). Yield=30mg (64%, two steps). LC/MS method A: R_(t)=4.31 min., (M+H)⁺=431.16.

Example 87: Synthesis of1-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(1-(aminomethyl)cyclopropane-1-carboxamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide was prepared according to theprocedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidehydrochloride (55 mg, 0.15 mmol) andN-t-butyloxycarbonyl-1-(aminomethyl)cyclopropane carboxylic acid (48 mg,0.22 mmol). Yield=48 mg (69%, two steps). LC/MS method A: R_(t)=4.19min., (M+H)⁺=429.19.

Example 88: Synthesis of1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)cyclohexane-1-carboxamide

1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)cyclohexane-1-carboxamide was prepared according to the procedure ofexample 49 from 1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamide hydrochloride (55 mg, 0.15 mmol)and N-t-butyloxycarbonyl-1-(aminomethyl)cyclohexane carboxylic acid (58mg, 0.22 mmol). Yield=43 mg (57%, two steps). LC/MS method A: R_(t)=4.50min., (M+H)⁺=471.21.

Example 89: Synthesis of(R)-1-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

(R)-1-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidehydrochloride (55 mg, 0.15 mmol) and N-t-butyloxycarbonyl-D-alanine (42mg, 0.22 mmol). Yield=27 mg (41%, two steps). LC/MS method A: R_(t)=4.10min., (M+H)⁺=403.15.

Example 90: Synthesis of(R)-1-(2-amino-3-methylbutanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

(R)-1-(2-amino-3-methylbutanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamidewas prepared according to the method of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidehydrochloride (55 mg, 0.15 mmol) and N-t-butyloxycarbonyl-D-valine (49mg, 0.22 mmol). Yield=57 mg (81%, two steps). LC/MS method A: R_(t)=4.32min., (M+H)⁺=431.16.

Example 91: Synthesis of(S)-2-(2-aminoacetamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-(2-aminoacetamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(19 mg, 0.05 mmol) and N-t-butyloxycarbonylglycine (13 mg, 0.065 mmol).Yield=20 mg (84%, two steps). LC/MS method A: R_(t)=4.36 min.,(M+H)⁺=438.98.

Example 92: Synthesis of(S)-2-(2-(methylamino)acetamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-(2-(methylamino)acetamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide was prepared according to the procedure ofexample 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(19 mg, 0.05 mmol) and N-t-butyloxycarbonyl-N-methylglycine (14 mg,0.065 mmol). Yield=13 mg (53%, two steps). LC/MS method A: R_(t)=4.41min., (M+H)⁺=453.05.

Example 92: Synthesis of(S)-2-((R)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-((R)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(42 mg, 0.10 mmol) and N-t-butyloxycarbonyl-D-alanine (28 mg, 0.15mmol). Yield=43 mg (88%, two steps). LC/MS method A: R_(t)=4.32 min.,(M−14+H)⁺=438.98.

Example 93: Synthesis of(S)-2-((S)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-((S)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(42 mg, 0.10 mmol) and N-t-butyloxycarbonyl-L-alanine (28 ng, 0.15mmol). Yield=43 mg (88%, two steps). LC/MS method A: R_(t)=4.32 min.,(M−14+H)⁺=438.98.

Example 94: Synthesis of(R)-2-amino-3-methyl-N—((S)-1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)butanamide

(R)-2-amino-3-methyl-N—((S)-1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)butanamide was prepared according to theprocedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(42 mg, 0.10 mmol) and N-t-butyloxycarbonyl-D-valine (33 mg, 0.15 mmol).Yield=46 mg (89%, two steps). LC/MS method A: R_(t)=3.62 min.,(M−14+H)⁺=467.06.

Example 95: Synthesis of(S)-2-amino-2-methyl-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide

(S)-2-amino-2-methyl-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(42 mg, 0.10 mmol) and N-t-butyloxycarbonylsarcosine (33 mg, 0.15 mmol).Yield=52 mg (100%, two steps). LC/MS method A: R_(t)=4.38 min.,(M−14+H)=452.99.

Example 96: Synthesis of(S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamide

(S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(42 mg, 0.10 mmol) and 1-N-t-butyloxycarbonylaminocyclopropanecarboxylic acid (30 mg, 0.15 mmol). Yield=41 mg (82%, two steps). LC/MSmethod A: R_(t)=4.33 min., (M−14+H)⁺=451.01.

Example 97: Synthesis of(S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutane-1-carboxamide

(S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutane-1-carboxamide was prepared according to theprocedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(42 mg, 0.10 mmol) and1-(N-t-butyloxycarbonylamino)cyclobutanecarboxylic acid (32 mg, 0.15mmol). Yield=41 mg (80%, two steps). LC/MS method A: R_(t)=4.43 min.,(M−14+H)⁺=465.16.

Example 98: Synthesis of1-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide was prepared according to theprocedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide(42 mg, 0.10 mmol) and3-((N-t-butyloxycarbonyl)amino)-2,2-dimethylpropanoic acid (32 mg, 0.15mmol). Yield=41 mg (80%, two steps). LC/MS method A: R_(t)=4.43 min.,(M−14+H)⁺=465.16.

Example 99: Synthesis of(R)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(R)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide was prepared according to the procedure ofexample 49 from 2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (50 mg, 0.14 mmol) andN-t-butyloxycarbonyl-D-anlanine (40 mg, 0.21 mmol). Yield=35 mg (59%,two steps). LC/MS method A: R_(t)=3.99 min., (M+H)⁺=390.98.

Example 100: Synthesis of(S)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(50 mg, 0.14 mmol) and N-(t-butyloxycarbonyl)alanine (40 mg, 0.21 mmol).Yield=36 mg (60%, two steps). LC/MS method A: R_(t)=4.00 min.,(M+H)⁺=390.98.

Example 101: Synthesis of 2-(2-aminoacetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-(2-aminoacetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (50 mg, 0.14 mmol) andN-(t-butyloxycarbonyl)glycine (37 mg, 0.21 mmol). Yield=40 mg (69%, twosteps). LC/MS method A: R_(t)=3.93 min., (M+H)⁺=376.91.

Example 102: Synthesis of(R)-2-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)-3-phenylpropanamide

(R)-2-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)-3-phenylpropanamide was prepared according to the procedureof example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(36 mg, 0.10 mmol) and N-(t-butyloxycarbonyl)-D-phenylalanine (34 mg,0.13 mmol). Yield=24 mg (49%, two steps). LC/MS method A: R_(t)=4.62min., (M+H)⁺=467.13.

Example 103: Synthesis of(S)-2-amino-3-(benzyloxy)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-)propanamide

(S)-2-amino-3-(benzyloxy)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide was prepared according to theprocedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(36 mg, 0.10 mmol) and(S)-2-(N-t-butyloxycarbonyl)amino-3-(benzyloxy)propanoic acid (38 mg,0.13 mmol). Yield=51 mg (95%, two steps). LC/MS method A: R_(t)=4.76min., (M+H)⁺=497.13.

Example 104: Synthesis of1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamide

1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and1-N-(t-butyloxycarbonyl)aminocyclopropanecarboxylic acid (40 mg, 0.19mmol). Yield=41 mg (62%, two steps). LC/MS method A: R_(t)=4.03 min.,(M+H)⁺=403.01.

Example 105: Synthesis of1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutan-1-carboxamide

1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutane-1-carboxamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and1-N-(t-butyloxycarbonyl)aminocyclobutanecarboxylic acid (41 mg, 0.19mmol). Yield=37 mg (54%, two steps). LC/MS method A: R_(t)=4.13 min.,(M+H)⁺=417.15.

Example 106: Synthesis of2-amino-2-methyl-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide

2-amino-2-methyl-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and 2-N-(t-butyloxycarbonyl)amino-2-methylpropanoicacid (40 mg, 0.19 mmol). Yield=10 mg (15%, two steps). LC/MS method A:R_(t)=4.02 min., (M+H)⁺=405.05.

Example 107: Synthesis of3-amino-2,2-dimethyl-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide

3-amino-2,2-dimethyl-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and3-N-(t-butyloxycarbonyl)amino-2,2-dimethylpropanoic acid (40 mg, 0.18mmol). Yield=5.8 mg (8.5%, two steps). LC/MS method A: R_(t)=4.06 min.,(M+H)⁺=419.12.

Example 108: Synthesis of1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamide

1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and1-((N-t-butyloxycarbonylamino)methyl)cyclopropanecarboxylic acid (39 mg,0.18 mmol). Yield=20 mg (29%, two steps). LC/MS method A: R_(t)=4.05min., (M+H)⁺=417.09.

Example 109: Synthesis of1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopentane-1-carboxamide

1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopentane-1-carboxamide was prepared according to theprocedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and1-((N-t-butyloxycarbonylamino)methyl)cyclopentanecarboxylic acid (44 mg,0.18 mmol). Yield=8.0 mg (11%, two steps). LC/MS method A: R_(t)=4.24min., (M+H)⁺=445.17.

Example 110: Synthesis of1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclohexane-1-carboxamide

1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) propan-2-yl)cyclohexane-1-carboxamide was preparedaccording to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and1-((N-1-butyloxycarbonyl)aminomethyl)cyclohexanecarboxylic acid (44 mg,0.18 mmol). Yield=8.0 mg (11%, two steps). LC/MS method A: R_(t)=3.26min., (M+H)⁺=459.24.

Example 111: Synthesis of2-methyl-2-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-methyl-2-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and N-(t-butyloxycarbonyl)-N-methylglycine (34 mg,0.18 mmol). Yield=25 mg (39%, two steps). LC/MS method A: R_(t)=3.99min., (M+H)⁺=391.05.

Example 112: Synthesis of2-(2-(ethylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-(2-(ethylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide was prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and N-(t-butyloxycarbonyl)-N-ethylglycine (37 mg,0.18 mmol). Yield=29 mg (44%, two steps). LC/MS method A: R_(t)=4.07min., (M+H)⁺=405.12.

Example 113: Synthesis of2-(2-(isopropylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-(2-(isopropylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and N-t-butyloxycarbonyl-N-isopropylglycine (39 mg,0.18 mmol). Yield=29 mg (42%, two steps). LC/MS method A: R_(t)=4.17min., (M+H)⁺=419.12.

Example 114: Synthesis of2-(2-(tert-butylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-(2-(tert-butylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and N-t-butyloxycarbonyl-N-t-butyl glycine (39 mg,0.18 mmol). Yield=18 mg (22%, two steps). LC/MS method A: R_(t)=4.26min., (M+H)⁺=433.13

Example 115: Synthesis of(S)-2-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl)propanamide (50mg, 0.146 mmol) and N-t-butyloxycarbonylglycine (33 mg, 0.19 mmol).Yield=35 mg (50%, two steps). LCMS method A: R_(t)=3.73 min.,(M+H)⁺=362.98.

Example 116: Synthesis of(S)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide

(S)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl)propanamide (50mg, 0.146 mmol) and N-t-butyloxycarbonylalanine (41 mg, 0.22 mmol).Yield=38 mg (53%, two steps). LC/MS method A: R_(t)=3.76 min.,(M+Na)⁺=398.93.

Example 117: Synthesis of(R)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide

(R)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl)propanamide (50mg, 0.146 mmol) and N-t-butyloxycarbonyl-D-alanine (41 mg, 0.22 mmol).Yield=23 mg (32%, two steps). LC/MS method A: R_(t)=3.76 min.,(M+H)⁺=376.98.

Example 118: Synthesis of3-Amino-N,2,2-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (25 mg, 73 μmol),3-((tert-butoxycarbonyl)amino)-2,2-dimethylpropanoic acid (19 mg, 88μmol) and N,N-diisopropylethylamine (24 mg, 180 μmol, 33 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (33 mg, 88 μmol) and stirred for 18 hours.The product was purified by reversed phase HPLC (method B, directinjection). The product was evaporated on a Genevac evaporator to leave36 mg (81%). The purified product was dissolved in 4N HCl/1,4-dioxane(0.5 ml) and stirred for 2 hours. The HCl/1,4-dioxane was evaporated toleave the product as a white solid, mono HCl salt. Yield=33 mg (100%,81% for two steps). LC/MS method A: R_(t)=3.88 min., (M+H)⁺=405.

Examples 119-125 were prepared under identical scale and method asexample 118 above:

Example 119: Synthesis of1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopropane-1-carboxamide

1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopropane-1-carboxamide was prepared according to theprocedure of example 118 from1-(((tert-butoxycarbonyl)amino)methyl)cyclopropane-1-carboxylic acid (19mg, 88 μmol). Yield=31 mg (98%, 80% for two steps). LC/MS method A:R_(t)=3.81 min., (M+H)⁺=403.

Example 120: Synthesis of1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopentane-1-carboxamide

1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopentane-1-carboxamide was prepared according to theprocedure of example 118 from1-(((tert-butoxycarbonyl)amino)methyl)cyclopentane-1-carboxylic acid (21mg, 88 μmol). Yield=33 mg (100%, 77% for two steps). LC/MS method A:R_(t)=4.07 min., (M+H)⁺=431.

Example 121: Synthesis of1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexane-1-carboxamide

1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl) amino)ethyl)cyclohexane-1-carboxamide was preparedaccording to the procedure of example 118 from1-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (23mg, 88 μmol). Yield=23 mg (100%, 48% for two steps). LC/MS method A:R_(t)=4.21 min., (M+H)⁺=445.

Example 122: Synthesis ofN-methyl-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

N-methyl-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example118 from N-(tert-butoxycarbonyl)-N-methylglycine (17 mg, 88 μmol).Yield=30 mg (100%, 86% for two steps). LC/MS method A: R_(t)=3.70 min.,(M+H)⁺=377.

Example 123: Synthesis of2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl) amino)ethyl)acetamide

2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example 118from N-(tert-butoxycarbonyl)-N-ethylglycine (18 mg, 88 μmol). Yield=32mg (100%, 86% for two steps). LC/MS method A: R_(t)=3.78 min.,(M+H)⁺=391.

Example 124: Synthesis of2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to theprocedure of example 118 from N-(tert-butoxycarbonyl)-N-isopropylglycine(19 mg, 88 μmol). Yield=34 mg (100%, 81% for two steps). LC/MS method A:R_(t)=3.88 min., (M+H)⁺=405.

Example 125: Synthesis of2-(tert-butylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-(tert-butylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidewas prepared according to the procedure of example 118 fromN-(tert-butoxycarbonyl)-N-tert-butylglycine (20 mg, 88 μmol). Yield=29mg (100%, 68% for two steps). LC/MS method A: R_(t)=3.99 min.,(M+H)⁺=419.

Example 126: Synthesis of2-(dimethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-(dimethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example49 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (50 mg, 0.16 mmol) and N,N-dimethylglycine hydrochloride(25 mg, 0.18 mmol). Purified by reverse phase HPLC to leave the productas a mono TFA salt. Yield=64 mg (79%). LC/MS method B: R_(t)=1.41 min.,(M+H)⁺=391.

Example 127: Synthesis of2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example 49 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (50 mg, 0.16 mmol) and N-(tert-butoxycarbonyl)glycine (36mg, 0.21 mmol). Yield=38 mg (65%, two steps). LC/MS method A: R_(t)=3.64min., (M+H)⁺=362.98.

Example 128: Synthesis of(S)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(S)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 49from 2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride (50 mg, 0.16 mmol) andN-(tert-butoxycarbonyl)alanine (41 mg, 0.22 mmol). Yield=45 mg (75%, twosteps). LC/MS method A: R_(t)=3.76 min., (M+Na)⁺=398.93.

Example 129: Synthesis of(R)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(R)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 49from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (50 mg, 0.16 mmol) and N-(tert-butoxycarbonyl)-D-alanine(41 mg, 0.22 mmol). Yield=45 mg (75%, two steps). LC/MS method A:R_(t)=3.76 min., (M+Na)⁺=398.93.

Example 130: Synthesis of3-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

3-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 49 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (34 mg, 0.10 mmol) andN-(tert-butoxycarbonyl)-beta-alanine (33 mg, 0.17 mmol). Yield=35 mg(58%, two steps). LC/MS method A: R_(t)=3.69 min., (M+H)⁺=376.91.

Example 131: Synthesis of2-amino-N-ethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-amino-N-ethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example 49 from2-(ethylamino)-N-(6-(trifluoromethoxy)benzo [d]thiazol-2-yl)acetamidehydrochloride (35 mg, 0.10 mmol) and N-(tert-butoxycarbonyl)glycine (23mg, 0.13 mmol). Yield=32 mg (77%, two steps). LC/MS method A: R_(t)=3.76min., (M+H)⁺=376.98.

Example 132: Synthesis of2-amino-N-isopropyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-amino-N-isopropyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example 49from 2-(isopropyl amino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride (37 mg, 0.10 mmol) andN-(tert-butoxycarbonyl)glycine (23 mg, 0.13 mmol). Yield=32 mg (75%, twosteps). LC/MS method A: R_(t)=3.88 min., (M+H)⁺=390.91.

Example 133: Synthesis of2-(aminomethyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide

A solution of 2-amino-6-(trifluoromethoxy)benzo[d]thiazole (100 mg, 0.43mmol), 2-N-((tert-butoxy carbonyl)aminomethyl)benzoic acid (161 mg, 0.64mmol) and N, N-diisopropyl ethylamine (83 mg, 0.64 mmol, 115 μl) inN,N-dimethylformamide (2 ml) was treated with 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate(243 mg, 0.64 mmol) and stirred for 72 hours. The reaction mixture wasdiluted with ethyl acetate (50 ml), washed with water (2×25 ml) and 1NHCl (25 ml). The solvents were evaporated and the residue waschromatographed on silica gel eluted with a gradient of 10% ethylacetate in hexanes to 50% ethyl acetate in hexanes. The product (87 mg,43%) was dissolved in 4N HCl/1,4-dioxane, stirred for 2 hours thenevaporated to dryness. The white powdery mono hydrochloride productweighed 77 mg (100%, 43% for two steps). LC/MS method A: R_(t)=3.97min., (M+H)⁺=368.

Example 134: Synthesis of tert-butyl(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)carbamate

A solution of 2-amino-6-(trifluoromethoxy)benzo[d]thiazole (2.0 g, 8.5mmol), N-(tert-butyloxycarbonyl)-4-aminobutyric acid (2.6 g, 12.8 mmol)and N,N-diisopropylethylamine (1.7 g, 12.8 mmol, 2.3 ml) inN,N-dimethylformamide (40 ml) was treated with 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate(4.9 g, 12.8 mmol) and stirred for 18 h. Ethyl acetate (200 ml) wasadded to the reaction mixture and it was washed with water (2×150 ml),1N HCl (2×100 ml), saturated aqueous sodium bicarbonate (100 ml) andbrine (100 ml). The organic layer was dried (Na₂SO₄) and evaporated toleave a light yellow crystalline solid (2.9 g, 81%). LC/MS method A:R_(t)=5.88 min., (M+H)⁺=420.42.

Synthesis of4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

A solution of tert-butyl(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)carbamate (2.8 g, 6.7 mmol) in 1,4-dioxane (35 ml) and 4NHCl/1,4-dioxane (35 ml) was stirred for 18 h. The white precipitate wasfiltered on a medium glass frit and washed with 1,4-dioxane and ether.The solid was dried under vacuum to leave 2.55 g (97%). LC/MS method A:R_(t)=3.68 min., (M+H)⁺=320.30.

Synthesis of(S)—N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamide

A solution of4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol) and N,N-diisopropylethylamine (17 mg, 0.13 mmol, 23 μl) inN,N-dimethylformamide (0.5 ml) was treated with 1-(tert-butyl)2-(2,5-dioxopyrrolidin-1-yl) (S)-pyrrolidine-1,2-dicarboxylate (22 mg,70 μmol) and stirred 18 h. The product was purified by direct injectionreverse phase HPLC (method B) and the product fractions were evaporatedon a Genevac evaporator to leave the product as a gum (29 mg) which wasdissolved in 1,4-dioxane (1 ml) and 4N HCl/1,4-dioxane (1 ml). Afterstirring for 4 h the solvents were evaporated to leave the product as awhite solid (26 mg, 83%). LC/MS method A: R_(t)=3.85 min., (M+H)⁺=417.

Example 135: Synthesis of(S)-2-amino-4-methyl-N-(4-oxo-4-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino)butyl)pentanamide

A solution of4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol) and N,N-diisopropylethylamine (17 mg, 0.13 mmol, 23 μl) inN,N-dimethylformamide (0.5 ml) was treated with 2,5-dioxopyrrolidin-1-yl(tert-butoxycarbonyl)-L-leucinate (23 mg, 70 μmol) and stirred 18 h. Theproduct was purified by direct injection reverse phase HPLC (method B)and the product fractions were evaporated on a Genevac evaporator toleave the product as a gum (29 mg) which was dissolved in 1,4-dioxane (1ml) and 4N HCl/1,4-dioxane (1 ml). After stirring for 4 h the solventswere evaporated to leave the product as a white solid (28 mg, 87%).LC/MS method A: R_(t)=4.14 min., (M+H)⁺=433.

Example 136: Synthesis of4-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

A solution of4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol), N-(tert-butoxycarbonyl)-L-glycine (13 mg, 76 μmol) andN,N-diisopropylethylamine (18 mg, 0.14 mmol, 25 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (27 mg, 70 μmol) and stirred 18 hours. Theproduct was purified by direct injection reverse phase HPLC (method B)and the product fractions were evaporated on a Genevac evaporator toleave the product as a gum (17 mg, 54%) which was dissolved in1,4-dioxane (1 ml) and 4N HCl/1,4-dioxane (1 ml). After stirring for 4hours the solvents were evaporated to leave the product as a white solid(12 mg, 46% for two steps). LC/MS method A: R_(t)=3.71 min., (M+H)⁺=377.

Examples 137-146 were prepared in identical scale and method to example136 above.

Example 137: Synthesis of(S)-4-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

(S)-4-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide was prepared according to the procedure ofexample 136 from 4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg, 65 μmol) andN-(tert-butoxycarbonyl)-L-alanine to leave 16 mg (59% for two steps).LC/MS method A: R_(t)=3.75 min., (M+H)⁺=391.

Example 138: Synthesis of(S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide

(S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide was prepared according to the procedure of example 136from 4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25mg, 65 μmol) and N-(tert-butoxy carbonyl)-L-Valine to leave 16 mg (59%for two steps). LC/MS method A: R_(t)=3.95 min., (M+H)⁺=419.

Example 139: Synthesis of(S)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamide

(S)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 136 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μol) and L-pyroglutamate to leave 14 mg (47% for two steps). LC/MSmethod A: R_(t)=4.22 min., (M+H)⁺=431.

Example 140: Synthesis of(2S,3S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pentanamide

(2S,3S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pentanamide was prepared according to the procedure of example 136from 4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25mg, 65 μmol) and N-(tert-butoxy carbonyl)-L-isoleucine to leave 14 mg(47% for two steps). LC/MS method A: R_(t)=4.11 min., (M+H)⁺=433.

Example 141: Synthesis of(S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)pentanoic add

(S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)pentanoic acid was prepared according to the procedure of example136 from 4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide(25 mg, 65 μmol) and N-(tert-butoxycarbonyl)-L-glutamine to leave 16 mg(52% for two steps). LC/MS method A: R_(t)=3.62 min., (M+H)⁺=448.

Example 142: Synthesis of(S)-2-amino-4-(methylthio)-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide

(S)-2-amino-4-(methylthio)-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide was prepared according to the procedure ofexample 136 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol) and N-(tert-butoxycarbonyl)-L-methionine to leave 16 mg (51%for two steps). LC/MS method A: R_(t)=4.02 min., (M+H)⁺=451.

Example 143:(S)-4-(2-amino-3-phenylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

(S)-4-(2-amino-3-phenylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamidewas prepared according to the procedure of example 136 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol) and N-(tert-butoxycarbonyl)-L-phenylalanine to leave 16 mg (50%for two steps). LC/MS method A: R_(t)=4.20 min., (M+H)⁺=467.

Example 144: Synthesis of(S)-3-amino-4-oxo-4-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)butanoic acid

(S)-3-amino-4-oxo-4-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)butanoic acid was prepared according to the procedure of example136 from 4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide(25 mg, 65 μmol) and N-(tert-butoxycarbonyl)-aspartic acid betatert-butyl ester to leave 18 mg (60% for two steps). LC/MS method A:R_(t)=3.72 min., (M+H)⁺=435.

Example 145: Synthesis of(S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)pentanoic acid

(S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)pentanoic acid was prepared according to the procedure of example136 from 4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide(25 mg, 65 μmol) and N-(tert-butoxy carbonyl)-L-glutamine gamma tertbutyl ester to leave 16 mg (52% for two steps). LC/MS method A:R_(t)=3.72 min., (M+H)⁺=449.

Example 146: Synthesis of(S)-4-(2-amino-3-(1H-indol-3-yl)propanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

(S)-4-(2-amino-3-(1H-indol-3-yl)propanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide was prepared according to the procedure ofexample 136 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol) and N-(tert-butoxy carbonyl)-L-tryptophan to leave 20 mg (71%for two steps). LC/MS method A: R_(t)=4.24 min., (M+H)⁺=506.

Example 147: Synthesis of(S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamideSynthesis of tert-butyl ((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)carbamate

A solution of 2-amino-6-(trifluoromethoxy)benzo[d]thiazole (0.50 g, 2.1mmol), 2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid(0.74 g, 2.7 mmol) and N,N-diisopropylethylamine (0.35 g, 2.7 mmol,2.30.48 ml) in N,N-dimethylformamide (10 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (1.0 g, 2.7 mmol) and stirred for 18 hours.Ethyl acetate (100 ml) was added to the reaction mixture and it waswashed with water (2×50 ml), 1N HCl (100 ml), saturated aqueous sodiumbicarbonate (100 ml) and brine (50 ml). The organic layer was dried(Na₂SO₄) and evaporated. The crude product was chromatographed on silicagel with a gradient of 20% to 25% ethyl acetate in hexanes to leave theproduct as a white crystalline solid (0.44 g, 43%). LC/MS method A:R_(t)=7.36 min., (M+H)⁺=488.

Synthesis of2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide

A solution of tert-butyl((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)carbamate (0.42 g, 0.86 mmol) in 1,4-dioxane (10ml) and 4N HCl/1,4-dioxane (10 ml) was stirred for 18 hours. Thesolvents were evaporated to leave the product as a white solid (0.38 g,100%). LC/MS method A: R_(t)=4.27 min., purity >95%, (M+H)⁺=388.

Synthesis of(S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide

A solution of2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide (20 mg, 47 μmol) and N,N-diisopropylethylamine(15 mg, 0.12 mmol, 21 μl) in N,N-dimethylformamide (0.5 ml) was treatedwith 1-(tert-butyl) 2-(2,5-dioxopyrrolidin-1-yl)(S)-pyrrolidine-1,2-dicarboxylate (18 mg, 56 μmol) and stirred 18 h. Theproduct was purified by direct injection reverse phase HPLC (method B)and the product fractions were evaporated on a Genevac evaporator toleave the product which was dissolved in 1,4-dioxane (1 ml) and 4NHCl/1,4-dioxane (1 ml). After stirring for 4 h the solvents wereevaporated to leave the product as a white solid (21 mg, 92%). LC/MSmethod A: R_(t)=4.75 min., (M+H)⁺=485.

Examples 148-149 were prepared in identical scale and method to example147 above.

Example 148: Synthesis of(S)-2-amino-4-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pentanamide

(S)-2-amino-4-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pentanamidewas prepared according to the procedure of example 147 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and 2,5-dioxopyrrolidin-1-yl L-leucinateto leave 23 mg(94% for two steps). LC/MS method A: R_(t)=5.04 min., (M+H)⁺=501.

Example 149: Synthesis of(S)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide

(S)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide was prepared according to theprocedure of example 147 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and 2,5-dioxopyrrolidin-1-yl L-valinate to leave 15 mg(66% for two steps). LC/MS method A: R_(t)=4.87 min., (M+H)⁺=487.

Example 150: Synthesis of2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)acetamide

A solution of2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol), N-(tert-butoxycarbonyl)-L-glycine (10 mg, 57 μmol) andN,N-diisopropylethylamine (15 mg, 0.12 mmol, 22 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (22 mg, 57 μmol) and stirred 18 hours. Theproduct was purified by direct injection reverse phase HPLC (method B)and the product fractions were evaporated on a Genevac evaporator toleave the product as a gum (13 mg, 51%) which was dissolved in1,4-dioxane (1 ml) and 4N HCl/1,4-dioxane (1 ml). After stirring for 4hour the solvents were evaporated to leave the product as a white solid(10 mg, 47% for two steps). LC/MS method A: R_(t)=4.53 min., (M+H)⁺=445.

Examples 151-160 were prepared in identical scale and method to example150 above.

Example 151: Synthesis of(S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)propanamide

(S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)propanamide was prepared according to the procedure ofexample 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and (tert-butoxycarbonyl)-L-alanine to leave 9 mg (39%for two steps). LC/MS method A: R_(t)=4.61 min., (M+H)⁺=459.

Example 152: Synthesis of2-(methylamino)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)acetamide

2-(methylamino)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)acetamide was prepared according to the procedure ofexample 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and (tert-butoxycarbonyl)-sarcosine to leave 15 mg (65%for two steps). LC/MS method A: R_(t)=4.60 min., (M+H)⁺=459.

Example 153: Synthesis of(R)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide

(R)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamidewas prepared according to the procedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and (tert-butoxycarbonyl)-D-valine to leave 11 mg (45%for two steps). LC/MS method A: R_(t)=4.86 min., (M+H)⁺=487.

Example 154: Synthesis of(S)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide

(S)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide was prepared according tothe procedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and L-pyroglutamate to leave 12 mg (45% for two steps).LC/MS method A: R_(t)=4.41 min., (M+H)⁺=499.

Example 155: Synthesis of(S)-2-amino-N1-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pentanediamide

(S)-2-amino-N1-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pentanediamide was prepared according to the procedureof example 150 from2-1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and (tert-butoxycarbonyl)-L-glutamine to leave 5 mg(19% for two steps). LC/MS method A: R_(t)=4.42 min., (M+H)⁺=516.

Example 156: Synthesis of(S)-2-amino-4-(methylthio)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide

(S)-2-amino-4-(methylthio)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamidewas prepared according to the procedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide (20 mg, 47 μmol) and(tert-butoxycarbonyl)-L-methionine to leave 12 mg (46% for two steps).LC/MS method A: R_(t)=4.90 min., (M+H)⁺=519.

Example 157: Synthesis of(S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)-3-phenylpropanamide

(S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)-3-phenylpropanamide was prepared according to theprocedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and (tert-butoxycarbonyl)-L-phenylalanine to leave 13mg (49% for two steps). LC/MS method A: R_(t)=5.10 min., (M+H)⁺=535.

Example 158: Synthesis of(S)-3-amino-4-oxo-4-(((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)amino)butanoic acid

(S)-3-amino-4-oxo-4-(((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)amino)butanoic acid was prepared according tothe procedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and N-(tert-butoxycarbonyl)-L-aspartyl-beta-tert-butylester to leave 13 mg (51% for two steps). LC/MS method A: R_(t)=4.51min., (M+H)⁺=503.

Example 159: Synthesis of(S)-4-amino-5-oxo-5-(((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)amino)pentanoic acid

(S)-4-amino-5-oxo-5-(((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)amino)pentanoic acid was prepared according tothe procedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and N-(tert-butoxycarbonyl)-L-glutamyl-gamma-tert-butylester to leave 14 mg (54% for two steps). LC/MS method A: R_(t)=4.52min., (M+H)⁺=517.

Example 160: Synthesis of(S)-2-amino-3-(1H-indol-3-yl)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)propanamide

(S)-2-amino-3-(1H-indol-3-yl)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)propanamidewas prepared according to the procedure of example 150 from2-(1-aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and N-(tert-butoxycarbonyl)-L-tryptophan to leave 11 mg(38% for two steps). LC/MS method A: R_(t)=5.06 min., (M+H)⁺=574.

Example 161: Synthesis of(R)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide

A solution of4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (20 mg,56 μmol), N-(tert-butoxycarbonyl)-D-valine (16 mg, 73 μmol) andN,N-diisopropylethylamine (22 mg, 0.17 mmol, 30 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (28 mg, 73 μmol) and stirred 18 hours. Theproduct was purified by direct injection reverse phase HPLC (method B)and the product fractions were evaporated on a Genevac evaporator toleave the product as a gum (21 mg, 72%) which was dissolved in1,4-dioxane (1 ml) and 4N HCl/1,4-dioxane (1 ml). After stirring for 4hours the solvents were evaporated to leave the product as a white solid(19 mg, 72% for two steps). LC/MS method A: R_(t)=4.01 min., (M+H)⁺=419.

Examples 162-163 were prepared in identical scale and method to example161 above.

Example 162: Synthesis of(R)—N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamide

(R)—N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 161 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (20 mg,56 μmol) and N-(tert-butoxy carbonyl)-D-proline to leave 25 mg (76% fortwo steps). LC/MS method A: R_(t)=3.91 min., (M+H)⁺=417.

Example 163: Synthesis of(R)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamide

(R)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 161 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (20 mg,56 μmol) and D-pyroglutamate to leave 9 mg (37% for two steps). LC/MSmethod A: R_(t)=4.28 min., (M+H)⁺=431.

Example 164: Synthesis of(R)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide

A solution of2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(25 mg, 56 μmol), N-(tert-butoxycarbonyl)-D-valine (16 mg, 73 μmol) andN,N-diisopropylethylamine (22 mg, 0.17 mmol, 30 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidhexafluoro phosphate (28 mg, 73 μmol) and stirred 18 hours. The productwas purified by direct injection reverse phase HPLC (method B) and theproduct fractions were evaporated on a Genevac evaporator to leave theproduct as a gum (10 mg, 30%) which was dissolved in 1,4-dioxane (1 ml)and 4N HCl/1,4-dioxane (1 ml). After stirring for 4 hours the solventswere evaporated to leave the product as a white solid (8 mg, 27% for twosteps). LC/MS method A: R_(t)=4.86 min., (M+H)⁺=487.

Examples 165-166 were prepared in identical scale and method to example164 above.

Example 165: Synthesis of(S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide

(S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide was prepared according to the procedureof example 164 from 2-(1aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(25 mg, 56 μmol) and (tert-butoxycarbonyl)-D-proline to leave 10 mg (34%for two steps). LC/MS method A: R_(t)=3.91 min., (M+H)⁺=417.

Example 166: Synthesis of(R)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide

(R)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide: was prepared according tothe procedure of example 164 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(25 mg, 56 μmol) and D-pyroglutamate to leave 12 mg (43% for two steps).LC/MS method A: R_(t)=5.52 min., (M+H)⁺=499.

Example 167: Synthesis of4-amino-3,3-dimethyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

A solution of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (37 mg, 0.16mmol), 4-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (55 mg,0.24 mmol), 1-hydroxy-7-azabenzotriazole (33 mg, 0.24 mmol) andN,N-diisopropylethylamine (31 mg, 0.24 mmol, 43 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-methyl-2-chloropyridinium iodide (61 mg, 0.24 mmol) and stirred 4days. The product was purified by direct injection reverse phase HPLC(method B) and the product fractions were evaporated on a Genevacevaporator to leave the product as a solid (38 mg, 53%) which wasdissolved in 4N HCl/1,4-dioxane (1 ml). After stirring for 4 hours thesolvents were evaporated to leave the product as a white solid (34 mg,100%, 53% for two steps). LC/MS method A: R_(t)=3.95 min., (M+H)⁺=348.

Example 168: Synthesis of(S)-3-(benzyloxy)-2-morpholino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamideSynthesis of (R)-3-(benzyloxy)-2-bromopropanoic acid

A solution of O-benzyl-D-serine (1.0 g, 5.1 mmol) and potassium bromide(3.6 g, 30.6 mmol) in 2.5 N sulfuric acid (35 ml) in an ice bath wasstirred and treated with sodium nitrite (0.95 g, 14 mmol) in portionsover 30 mins. The mixture stirred an additional 60 mins., then ether (50ml) was added and thee mixture stirred 30 mins. The organic layer wasseparated, washed with brine (25 ml), dried (Na₂SO₄) and evaporated toleave the product as a colorless oil (1.3 g, 98%).

Synthesis of Methyl (R)-3-(benzyloxy)-2-bromopropanoate

A solution of (R)-3-(benzyloxy)-2-bromopropanoic acid (1.2 g, 4.6 mmol)in anhydrous tetrahydrofuran (30 ml) and methanol (5 ml) in an ice bathwas treated with an ethereal solution of trimethylsilyldiazomethane (3.5ml, 7.0 mmol) and stirred for 30 minutes. Acetic acid (1 ml) was addedto the reaction mixture stirred an additional 30 mins. Approximatelyhalf of the solvent was evaporated in vacuo, ethyl aceatet (50 ml) wasadded and the solution was washed with saturated sodium bicarbonatesolution (25 ml) and brine (25 ml). The organic phase was dried (MgSO₄)and evaporated. The crude product was purified by silica gelchromatography eluted with 10% ethyl acetate in hexanes to leave aclear, colorless oil (0.90 g, 72%). LC/MS method A: R_(t)=5.57 min.

Synthesis of Methyl (R)-3-(benzyloxy)-2-morpholinopropanoate

A solution of Methyl (R)-3-(benzyloxy)-2-bromopropanoate (100 mg, 0.36mmol) and morpholine (0.16 g, 1.8 mmol, 0.16 ml) inN,N-dimethylformamide (2 ml) was stirred for 5 days. The reactionmixture was diluted with ethyl acetate (25 ml) and washed with water (25ml), saturated sodium bicarbonate solution (25 ml) and brine (25 ml).The organic phase was dried (MgSO₄) and evaporated to leave the productas an oil (0.10 g, 100%). LC/MS method A: R_(t)=2.95 min., (M+H)⁺=280.

Synthesis of (S)-3-(benzyloxy)-2-morpholinopropanoic acid

A solution of Methyl (R)-3-(benzyloxy)-2-morpholinopropanoate (95 mg,0.34 mmol) and lithium hydroxide monohydrate (57 mg, 1.4 mmol) intetrahydrofuran (2 ml) and water (3 ml) was stirred for 1.5 hours. Thereaction mixture was purified by reverse phase HPLC (method B) and theproduct fractions were evaporated on a Genevac evaporator to leve thepure product as a TFA salt (62 mg, 48%). LC/MS method A: R_(t)=2.5 min.,(M+H)⁺=266.

Synthesis of(S)-3-(benzyloxy)-2-morpholino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

A solution of (S)-3-(benzyloxy)-2-morpholinopropanoic acid TFA salt (55mg, 0.15 mmol), 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (68 mg, 0.30mmol), 1-hydroxy-7-azabenzotriazole (23 mg, 0.17 mmol) andN,N-diisopropylethylamine (58 mg, 0.45 mmol, 81 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-methyl-2-chloropyridinium iodide (43 mg, 0.17 mmol) and the mixturewas stirred for 18 hours. The reaction mixture was purified by reversephase HPLC. The acetonitrile was evaporated from the product fractionsand the aqueous residue was diluted with saturated sodium bicarbonatesolution (25 ml) and ethyl acetate (50 ml). The organic phase wasseparated, washed with brine (25 ml), dried (MgSO₄) and evaporated. Theresidue was dissolved in 1,4-dioxane (2 ml) and treated with 4N HCl in1,4-dioxane (1 ml). The mixture was evaporated to leave the monohydrochloride salt of the product (60 mg, 77%). LC/MS method A:R_(t)=4.82 min., (M+H)⁺=482.

Example 169: Synthesis of(S)-3-(benzyloxy)-2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide Synthesis of MethylO-benzyl-N,N-dimethyl-L-serinate

A solution of methyl (R)-3-(benzyloxy)-2-bromopropanoate (100 mg, 0.36mmol) and dimethylamine (5.6 M in ethanol, 1.9 mmol, 0.34 ml) inN,N-dimethylformamide (2 ml) was stirred for 18 hours. The reactionmixture was diluted with ethyl acetate (25 ml) and washed with water (25ml) and brine (25 ml). The organic phase was dried (MgSO₄) andevaporated to leave the product as an oil (83 mg, 95%). LC/MS method A:R_(t)=2.94 min., (M+H)⁺=238.

Synthesis of O-benzyl-N,N-dimethyl-L-serine

A solution of methyl O-benzyl-N,N-dimethyl-L-serinate (75 mg, 0.32 mmol)and lithium hydroxide monohydrate (53 mg, 1.3 mmol) in tetrahydrofuran(2 ml) and water (3 ml) was stirred for 1 hour. The reaction mixture waspurified by reverse phase HPLC (method B) and the product fractions wereevaporated on a Genevac evaporator to leave the pure product as a TFAsalt (110 mg, 100%). LC/MS method A: R_(t)=2.53 min.

Synthesis of(S)-3-(benzyloxy)-2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

A solution of O-benzyl-N,N-dimethyl-L-serine TFA salt (52 mg, 0.22mmol), 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (50 mg, 0.15 mmol),1-hydroxy-7-azabenzotriazole (29 mg, 0.22 mmol) andN,N-diisopropylethylamine (58 mg, 0.45 mmol, 81 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-methyl-2-chloropyridinium iodide (56 mg, 0.22 mmol) and the mixturewas stirred for 18 hours. The reaction mixture was purified by reversephase HPLC. The acetonitrile was evaporated from the product fractionsand the aqueous residue was diluted with saturated sodium bicarbonatesolution (25 ml) and ethyl acetate (50 ml). The organic phase wasseparated, washed with brine (25 ml), dried (MgSO₄) and evaporated. Theresidue was dissolved in 1,4-dioxane (2 nil) and treated with 4N HCl in1,4-dioxane (1 ml). The mixture was evaporated to leave the monohydrochloride salt of the product (21 mg, 29%). LC/MS method A:R_(t)=2.70 min., (M+H)⁺=440.

Example 170: Synthesis of(S)-1-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

A solution of N-methyl-L-proline (55 mg, 0.42 mmol),6-(trifluoromethoxy)benzo[d] thiazol-2-amine (50 mg, 0.21 mmol),1-hydroxy-7-azabenzotriazole (56 mg, 0.42 mmol) andN,N-diisopropylethylamine (54 mg, 0.42 mmol, 75 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-methyl-2-chloropyridinium iodide (107 mg, 0.42 mmol) and the mixturewas stirred for 18 hours. The reaction mixture was purified by reversephase HPLC. The product fractions were combined, treated with saturatedsodium bicarbonate (25 ml) and extracted with ethyl acetate (2×25 ml).The combined extracts were washed with brine (25 ml), dried (MgSO₄) andevaporated. The residue was dissolved in 1,4-dioxane (2 ml) and treatedwith 4N HCl in 1,4-dioxane (1 ml). The mixture was evaporated to leavethe mono hydrochloride salt of the product (67 mg, 84%). LC/MS method A:R_(t)=3.77 min., (M+H)⁺=346.

Example 171: Synthesis of2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(50 mg, 0.16 mmol), N-(tert-butoxycarbonyl)-N-ethylglycine (37 mg, 0.18mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol, 65 μl) inN,N-dimethylformamide (1 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (68 mg, 0.18 mmol) and stirred 18 hours. Theproduct was purified by direct injection reverse phase HPLC (method B)and the product fractions were evaporated on a Genevac evaporator toleave the product as a gum (56 mg, 71%) which was dissolved in 4NHCl/1,4-dioxane (2 ml). After stirring for 2 hours the solvents wereevaporated to leave the product as a white solid (43 mg, 63% for twosteps). LC/MS method C: R_(t)=1.41 min., (M+H)⁺=391.

Example 172 was prepared under identical scale and conditions as example171 above.

Example 172: Synthesis of2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide:was prepared according to the procedure of example 171 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(50 mg, 0.16 mmol) and N-(tert-butoxycarbonyl)-N-isopropylglycine toleave 43 mg (63% for two steps). LC/MS method C: R_(t)=1.44 min.,(M+H)⁺=405.

Example 173: Synthesis of(R)-1-(1-(aminomethyl)cyclohexane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

A solution of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(200 mg, 0.54 mmol),1-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (168mg, 0.65 mmol) and N,N-diisopropylethylamine (168 mg, 1.3 mmol, 233 μl)in N,N-dimethylformamide (3 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (247 mg, 0.65 mmol) and stirred 18 hours. Thereaction mixture was diluted with ethyl acetate (50 ml) and washed withwater (50 ml), 1N HCl (50 ml), water (50 ml), saturated sodiumbicarbonate solution (50 ml) and brine (25 ml). The organic layer wasdried (MgSO₄) and evaporated. The product was purified by chromatographyon silica gel eluted with a gradient of ethyl acetate in hexanes(10-40%) to leave the pure product as a foamy solid (220 mg, 71%). Thisproduct was dissolved in 4N HCl/1,4-dioxane (2 ml). After stirring for 2hours the solvents were evaporated to leave the product as a white solid(188 mg, 69% for two steps). LC/MS method A: R_(t)=4.40 min.,(M+H)⁺=471.

Example 174: Synthesis ofN-methyl-2-(methylsulfonamido)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(25 mg, 73 μmol), (methylsulfonyl)glycine (12 mg, 88 μmol) andN,N-diisopropylethylamine (24 mg, 183 mmol, 33 μl) inN,N-dimethylformamide (0.5 ml) was treated with 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate (33 mg, 88 μmol) and stirred 18 hours. The reactionmixture was diluted with ethyl acetate (25 ml) and washed with water (25ml), 1N HCl (25 ml) and brine (25 ml). The organic layer was dried(MgSO₄) and evaporated. The product was purified by reverse phase HPLC(method B) to leave the pure product as a crystalline solid (11 mg,34%). LC/MS method C: R_(t)=2.06 min., (M+H)⁺=441.

Example 175: Synthesis of2-(tert-butoxy)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (50 mg, 0.15 μmol), 2-(tert-butoxy)acetic acid (22 mg,0.17 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol, 63 μl) inN,N-dimethylformamide (1 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluoro phosphate (57 mg, 0.15 mmol) and stirred 3 hours. Theproduct was purified by reverse phase HPLC (method B) and the combinedproduct fractions were evaporated to leave the pure product as a stickysolid (59 mg, 93%). LC/MS method C: R_(t)=2.26 min., (M+H)⁺=420.

Example 176: Synthesis ofN,4,4-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanamide

N,4,4-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl) pentanamide was prepared according tothe procedure of example 175 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (50 mg, 0.15 mmol) and 4,4-dimethylpentanoic acid onthe same scale as example 175 to leave 50 mg (80%) of product. LC/MSmethod C: R_(t)=2.50 min., (M+H)⁺=418.

Example 177: Synthesis of tert-Butyl(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1-(trifluoromethyl)cyclopropyl)carbamateSynthesis of Benzyl (1-(trifluoromethyl)cyclopropyl)carbamate

A solution of 1-(trifluoromethyl)cyclopropan-1-amine hydrochloride (0.15g, 0.93 mmol) and N,N-diisopropylethylamine (0.28 g, 2.2 mmol, 0.39 ml)in dichloromethane (5 ml) was cooled in an ice bath and treated withbenzyl chloroformate (0.17 g, 1.0 mmol, 0.143 ml). The mixture wasallowed to warm to 20° C. over 2 hours and stirred an additional 72hours. The mixture was diluted with ethyl acetate (50 ml), washed with1N HCl (25 ml) and brine (25 ml). The organic phase was dried (MgSO₄)and evaporated to leave the product as a solid (135 mg, 56%).

Synthesis of tert-butylN-((benzyloxy)carbonyl)-N-(1-(trifluoromethyl)cyclopropyl) glycinate

A solution of benzyl (1-(trifluoromethyl)cyclopropyl)carbamate (130 mg,0.50 mmol) in anhydrous tetrahydrofruan (4 ml) under nitrogen atmospherein an ice bath was treated with a solution of lithiumhexamethyldisilylamide (1.0 M in tetrahydrofruan, 0.60 ml, 0.60 mmol)dropwise over 5 minutes. The mixture stirred 30 minutes then 1-bromotert-butylacetate was added and stirring continued for an additional 18hours. The reaction mixture was treated with saturated aqueous ammoniumchloride (1 ml) and stirred 30 minutes. Ethyl acetate (50 ml) was addedand the mixture was washed with water (25 ml) and brine (25 ml). Theorganic phase was dried (MgSO₄) and evaporated. The crude product waspurified by silica gel chromatography eluting with a gradient of ethylacetate in hexanes (0-30%) to leave the product as a colorless oil (143mg, 77%). LC/MS method C: R_(t)=2.69 min.

Synthesis ofN-((Benzyloxy)carbonyl)-N-(1-(trifluoromethyl)cyclopropyl)glycine

A solution of tert-butylN-((benzyloxy)carbonyl)-N-(1-(trifluoromethyl)cyclopropyl) glycinate(140 mg, 0.37 mmol) in TFA (1.5 ml) and dichloromethane (1.5 ml) wasstirred 2 hours then evaporated. Left 117 mg (100%). LC/MS method C:R_(t)=2.13 min.

Synthesis of tert-Butyl(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1-(trifluoromethyl)cyclopropyl)carbamate

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (120 mg, 0.35 mmol),N-((benzyloxy)carbonyl)-N-(1-(trifluoromethyl) cyclopropyl)glycine (111mg, 0.35 mmol) and N,N-diisopropylethylamine (181 mg, 1.4 mmol, 251 μl)in N,N-dimethylformamide (3 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (133 mg, 0.35 mmol) and stirred 4 hours. Themixture was diluted with ethyl acetate (50 ml), washed with water (25ml), 1N HCl (25 ml) and brine (25 ml). The organic phase was dried(MgSO₄) and evaporated and the crude product was purified bychromatography on silica gel eluted with a gradient of ethyl acetate inhexanes (20%-100%) to leave the pure product as a gum (193 mg, 91%).LC/MS method C: R_(t)=2.60 min., (M+H)⁺=605.

Synthesis ofN-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((1-(trifluoromethyl)cyclopropyl)amino)acetamide

A solution of tert-Butyl(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1-(trifluoromethyl)cyclopropyl)carbamate(50 mg, 83 μmol) in concentrated hydrobromic acid in acetic acid (2 ml)stirred for 18 hours and evaporated. The residue was dissolved in water(2 ml) and purified by reverse phase HPLC (method B). The productfractions were evaporated to leave the pure product as a TFA salt (25mg, 52%). LC/MS method C: R_(t)=2.40 min., (M+H)⁺=471.

Example 178: Synthesis ofN-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((2,2,2-trifluoroethyl)amino)acetamidehydrochloride Synthesis of tert-Butyl (2,2,2-trifluoroethyl)carbamate

A solution of 2,2,2-trifluoroethylamine hydrochloride (1.0 g, 7.4 mmol)in 1,4-dioxane (15 ml) and water (15 nil) was treated with sodiumcarbonate (0.78 g, 7.4 ml) and stirred 5 minutes.Di-tert-butyldicarbonate (1.4 g, 6.6 mmol) was added and the mixturestirred 20 hours. Dichloromethane (50 ml) was added to the reactionmixture and it was washed with saturated sodium bicarbonate solution (50ml). The aqueous layer was back-extracted with dichloromethane (50 ml)and the combined dichloromethane layers were washed with brine, dried(MgSO₄) and evaporated to leave a white solid (964 mg, 65%).

Synthesis of BenzylN-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl)glycinate

A solution of tert-Butyl (2,2,2-trifluoroethyl)carbamate (300 mg, 1.50mmol) in anhydrous tetrahydrofruan (15 ml) under nitrogen atmosphere inan ice bath was treated with a solution of lithiumhexamethyldisilylamide (1.0 M in tetrahydrofruan, 1.8 ml, 1.8 mmol)dropwise over 5 minutes. The mixture stirred 30 minutes then 1-bromobenzylacetate (518 mg, 2.25 mmol, 0.357 ml) was added and stirringcontinued for an additional 18 hours. The reaction mixture was treatedwith saturated aqueous ammonium chloride (3 ml) and stirred 30 mins.Ethyl acetate (50 ml) was added and the mixture was washed with water(25 ml) and brine (25 ml). The organic phase was dried (MgSO₄) andevaporated. The crude product was purified by silica gel chromatographyeluting with a gradient of ethyl acetate in hexanes (0-30%) to leave theproduct as a colorless oil (335 mg, 65%). LC/MS method C: R_(t)=2.62min.

Synthesis of N-(tert-Butoxycarbonyl)-N-(22,2-trifluoroethyl)glycine

Benzyl N-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl)glycinate (170mg, 0.49 mmol) was hydrogenated (45 psi initial pressure) over 10% Pd/C(30 mg) in methanol (4 ml). After 18 hours the catalyst was filteredthrough celite (methanol wash) and the filtrate was evaporated to leavethe product as a crystalline solid (126 mg, 100%).

Synthesis ofN-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((2,2,2-trifluoroethyl)amino)acetamidehydrochloride

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (160 mg, 0.47 mmol),N-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl) glycine (120 mg, 0.47mmol) and N,N-diisopropylethylamine (152 mg, 1.2 mmol, 211 μl) inN,N-dimethylformamide (3 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (179 mg, 0.47 mmol) and stirred 18 hours. Themixture was diluted with ethyl acetate (50 ml), washed with water (25ml), 1N HCl (25 ml) and brine (25 ml). The organic phase was dried(MgSO₄) and evaporated and the crude product was purified by reversephase HPLC. The product fractions were combined, treated with sodiumbicarbonate solution and extracted with ethyl acetate (2×25 ml). Thecombined organic layers were washed with brine (25 ml), dried (MgSO₄)and evaporated. The product was dissolved in 4N HCl/1,4-dioxane andstirred 2 hours. The solid precipitate was filtered on a glass frit,washed with 1,4-dioxane and DCM, and dried under vacuum to leave 150 mg(66%). LC/MS method A: R_(t)=4.13 min., (M+H)⁺=445.

Example 179: Synthesis of2-acetamido-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

A solution of2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidehydrochloride (15 mg, 38 μmol) and N,N-diisopropylethylamine (17 mg, 132μmol, 24 μl) in N,N-dimethylformamide (0.4 ml) was treated with aceticanhydride (8.0 mg, 76 μmol·7.5 μl) and stirred 18 hours. Purified byreverse phase HPLC (direct injection of the reaction mixture) and theproduct fractions were evaporated to leave the pure product as a whitesolid (12 mg, 78%). LC/MS method B: R_(t)=1.82 min., (M+H)⁺=405.

Examples 180-184 were prepared on an identical scale and with the samemethod as example 179 above.

Example 180 Synthesis ofN-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propionamide

N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propionamide was preparedaccording to the procedure of example 179 from2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidehydrochloride (15 mg, 38 μmol) and propionic anhydride to leave 12 mg(76%). LC/MS method B: R_(t)=1.90 min., (M+H)⁺=419.

Example 181: Synthesis ofN-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)butyramide

N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)butyramidewas prepared according to the procedure of example 179 from2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidehydrochloride (15 mg, 38 μmol) and butyric anhydride to leave 12 mg(73%). LC/MS method B: R_(t)=1.99 min., (M+H)⁺=433.

Example 182: Synthesis ofN-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)isobutyramide

N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)isobutyramide was preparedaccording to the procedure of example 179 from2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidehydrochloride (15 mg, 38 μmol) and isobutyric anhydride to leave 12 mg(73%). LC/MS method B: R_(t)=1.98 min., purity >95%, (M+H)⁺=433.

Example 183: Synthesis ofN-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)benzamide

N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)benzamide was preparedaccording to the procedure of example 179 from2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidehydrochloride (15 mg, 38 μmol) and benzoic anhydride to leave 14 mg(79%). LC/MS method B: R_(t)=2.10 min., (M+H)⁺=467.

Example 184: Synthesis of2,2,2-trifluoro-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)acetamide

2,2,2-trifluoro-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl)amino)-2-oxoethyl)acetamide was preparedaccording to the procedure of example 179 from2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl) acetamide hydrochloride (15 mg, 38 μmol)and trifluoroacetic anhydride to leave 13 mg (75%).

LC/MS method B: R_(t)=2.12 min., (M+H)⁺=459.

Example 185: Synthesis ofN-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetamideSynthesis of Benzyl (1,1,1-trifluoro-2-methylpropan-2-yl)carbamate

A solution of 1,1,1-trifluoro-2-methylpropan-2-amine (1.0 g, 7.9 mmol,0.90 ml), N,N-diisopropylethylamine (1.5 g, 12 mmol, 1.7 ml) and4-(dimethylamino)pyridine (50 mg) in dichloromethane (40 ml) was cooledin an ice bath and treated with a solution of benzyl chloroformate (2.0g, 12 mmol, 1.7 ml) in dichloromethane (10 ml) dropwise over tenminutes. The mixture was allowed to warm to 20° C. over 2 hours andstirred an additional 24 hours. The mixture was washed with 1N HCl (25ml) and brine (25 ml). The organic phase was dried (MgSO₄) andevaporated. The crude product was purified by chromatography on silicagel eluted with a gradient of ethyl acetate in hexanes (5-10-20%) toleave the product as a solid (1.12 g, 56%). LC/MS method C: R_(t)=2.32min.

Synthesis of tert-butylN-((benzyloxy)carbonyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)glycinate

A solution of benzyl (1,1,1-trifluoro-2-methylpropan-2-yl)carbamate (1.1g, 4.2 mmol) in anhydrous tetrahydrofruan (40 ml) under nitrogenatmosphere in an ice bath was treated with a solution of lithiumhexamethyldisilylamide (1.0 M in tetrahydrofruan, 5.0 ml, 5.0 mmol)dropwise over 15 minutes. The mixture stirred 30 minutes then 1-bromotert-butylacetate (1.2 g, 6.3 mmol, 0.95 ml) was added and the mixturewarmed to 20° C. over 2 hours. Stirring continued for an additional 72hours. The reaction mixture was treated with saturated aqueous ammoniumchloride (5 ml) and stirred 30 mins. Approximately 75% of the solventswere evaporated and the remainder was treated with ethyl acetate (50ml). The mixture was washed with water (25 ml) and brine (25 ml). Theorganic phase was dried (MgSO₄) and evaporated. The crude product waspurified by silica gel chromatography eluting with a gradient of ethylacetate in hexanes (0-30%) to leave the product as an impure mixture(600 mg) which was further purified by reverse phase HPLC to leave theproduct as an oil (165 mg, 10.5%). LC/MS method A: R_(t)=6.57 min.

Synthesis ofN-((benzyloxy)carbonyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)glycine

A solution of tert-butylN-((benzyloxy)carbonyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)glycinate(160 mg, 0.43 mmol) in TFA (2 ml) and DCM (2 ml) was stirred 2 hoursthen evaporated. The residue was dissolved in toluene (5 ml) andevaporated (repeated 2×) to leave 132 mg (97%). LC/MS method A:R_(t)=4.87 min.

Synthesis of benzyl(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1,1,1-trifluoro-2-methylpropan-2-yl)carbamate

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (150 mg, 0.45 mmol),N-((benzyloxy)carbonyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)glycine(130 mg, 0.41 mmol) and N,N-diisopropylethylamine (120 mg, 0.90 mmol,160 μl) in N,N-dimethylformamide (2 ml) was treated with1-[Bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (170 mg, 0.45 mmol) and stirred 18 hours. Themixture was diluted with ethyl acetate (50 ml), washed with water (25ml), 1N HCl (25 ml) and brine (25 ml). The organic phase was dried(MgSO₄) and evaporated and the crude product was purified bychromatography on silica gel eluted with a gradient of ethyl acetate inhexanes (20%-70%) to leave the pure product as a gum (188 mg, 76%).LC/MS method A: R_(t)=6.28 min., (M+H)⁺=608.

Synthesis ofN-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetamide

A solution of benzyl(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1,1,1-trifluoro-2-methylpropan-2-yl)carbamate(180 mg, 0.30 mmol) in concentrated hydrobromic acid in acetic acid (4ml) stirred for 2 h and a precipitate has formed. The reaction mixturewas diluted with ethyl acetate (50 ml) and washed with aqueous saturatedsodium bicarbonate solution (200 ml). The organic phase was dried(MgSO₄) and evaporated to a solid. Dissolved in 1,4-dioxane (4 ml) andtreated with 4N HCl/1,4-dioxane. The product hydrochloride saltprecipitated and was collected on a medium glass frit, washed withdioxne and dichloromethane, and dried under vacuum to leave the productas a white powder (130 mg, 85%). LC/MS method A: R_(t)=4.45 min.,(M+H)⁺=473.

Example 186: Synthesis of2-(2-oxopiperazin-1-yl)-N-(6-(trifluoromethoxy)benzo [d]thiazol-2-yl)

A solution of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (150 mg, 0.64mmol), 2-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)acetic acid (232mg, 0.90 mmol) and N-hydroxybenzotriazole (122 mg, 0.90 mmol) inN,N-dimethylformamide (0.75 ml) was treated with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (173 mg, 0.90 mmol) andstirred 18 hours. The mixture was diluted with ethyl acetate (25 ml) andwashed with 0.5N HCl (25 ml) and saturated aqueous sodium bicarbonatesolution (25 ml). The organic phase was dried (MgSO₄) and evaporated andthe crude product was purified by silica gel chromatography eluted witha gradient of ethyl acetate in hexanes (0-100%) to leave the pureproduct which was dissolved in ethyl acetate (4 ml) and 4NHCl/1,4-dioxane (6 ml). The mixture stood for 3 hours and theprecipitate was filtered, washed (ethyl acetate) and dries to leave theproduct as a white powder (98 mg, 37%). LC/MS method A: R_(t)=3.60 min.,(M+H)⁺=375.

Example 187: Synthesis of(S)—N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (100 mg, 0.293 mmol),(S)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (135 mg,0.41 mmol), N-hydroxybenzotriazole (55 mg, 0.41 mmol) and triethylamine(33 mg, 0.32 mmol) in N,N-dimethylformamide (0.50 ml) was treated with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (79 mg, 0.41 mmol) andstirred 18 hours. The mixture was diluted with ethyl acetate (25 ml) andwashed with 0.5N HCl (25 ml) and saturated aqueous sodium bicarbonatesolution (25 ml). The organic phase was dried (MgSO₄) and evaporated andthe crude product was purified by silica gel chromatography eluted witha gradient of ethyl acetate in hexanes (20-80%) to leave the pureproduct (120 mg) which was dissolved in ethyl acetate (3 ml) and 4NHCl/1,4-dioxane (4 ml). The mixture stood for 3 hours and theprecipitate was filtered, washed (ethyl acetate) and dries to leave theproduct as a white powder (65 mg, 45%). LC/MS method A: R_(t)=3.39 min.,(M+H)⁺=418.

Example 188: Synthesis of(R)—N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide

(R)—N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide was prepared according to the procedure ofexample 187 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (100 mg, 0.293 mmol) and(R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid on the samescale as example 187 to provide 60 mg (42%). LC/MS method A: R_(t)=3.39min., (M+H)⁺=418.

Example 189: Synthesis of Benzyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate

To a solution of benzyl 2-hydroxyethylcarbamate (98 mg, 0.5 mmol) inchloroform (1.0 mL) was added triphosgene (60 mg, 0.2 mmol). The mixturewas stirred at 20° C. for 18 hours, then concentrated and dried undervacuum. The residue was dissolved in chloroform (1.0 mL) and was addedto a mixture of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (117 mg, 0.5mmol) and triethylamine (0.1 ml) in chloroform (2 mL). The resultingmixture was stirred at 20° C. for 18 hours. The mixture was concentratedand the residue was purified by reverse phase HPLC to give the desiredproduct. Yield=54 mg (24%). LC/MS method A: R_(t)=5.87 min.,(M+Na)⁺=478.

Example 190: Synthesis of 2-aminoethyl(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate

To a solution of benzyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate (32.7 mg, 0.072 mmol) in isopropanol (3 mL) was addedHBr in acetic acid (33%, 0.3 mL). The mixture was heated at 50° C. forovernight, and then concentrated. The residue was purified by reversedHPLC to give the desired product as TFA salt. Yield=28.8 mg (92%). LC/MSmethod A: R_(t)=3.74 min., (M+H)⁺=322.

Example 191: Synthesis of Benzylethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate

Benzylethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate was prepared according to the procedure of example 189 at thesame scale from 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and benzylethyl 2-hydroxyethylcarbamate. Yield=23 mg (9.5%). LC/MS method A:R_(t)=5.99 min., (M+H)⁺=484.

Example 192: Synthesis of 2-(Ethylamino)ethyl(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate

2-(Ethylamino)ethyl (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate,was prepared according to the procedure of example 190 at the same scalefrom benzylethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate(18 mg, 0.037 mmol). Yield=9.5 mg (58%). LC/MS method A: R_(t)=3.89min., (M+H)⁺=350.

Example 193: Synthesis of Benzylmethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate

Benzylmethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate was prepared according to the procedure of example 189 at thesame scale from 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and benzylmethyl 2-hydroxyethylcarbamate. Yield=36 mg (15%). LC/MS method A:R_(t)=5.98 min., (M+H)⁺=470.26.

Example 194: Synthesis of 2-(Methylamino)ethyl(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate

2-(Methylamino)ethyl (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamatewas prepared according to the procedure of example 190 from benzylmethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate(18 mg, 0.037 mmol). Yield=19 mg (69%). LC/MS method A: R_(t)=3.80 min.,(M+H)⁺=336.06.

Example 195: Synthesis of Benzylisopropyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate

Benzylisopropyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate was prepared according to the procedure of example 189 at thesame scale from 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and benzylisopropyl 2-hydroxyethylcarbamate. Yield=51 mg (21%). LC/MS method A:R_(t)=6.79 min., (M+Na)⁺=520.12.

Example 196: Synthesis of 2-(Isopropylamino)ethyl(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)carbamate

2-(Isopropylamino)ethyl(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate was preparedaccording to the procedure and same scale as example 190 from benzylisopropyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate. Yield=26 mg (62%). LC/MS method A: R_(t)=3.96 min.,(M+H)⁺=364.

Example 197: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(5-(trifluoro methoxy)benzo[d]thiazol-2-yl)carbamate

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(5-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate was preparedaccording to the procedure of example 189 at the same scale from6-(trifluoromethoxy)benzo[d]thiazol-2-amine and4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one. Yield=10 mg (5%). LC/MSmethod A: R_(t)=5.67 min.

Example 198: Synthesis of4-amino-2,2-dimethyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

4-Amino-2,2-dimethyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamidewas prepared according to the procedure of example 147 from2-amino-6-(trifluoromethoxy) benzimidazole (0.10 g, 0.43 mmol) and N-Boc4-amino-2,2-dimethylbutanoic acid (0.15 g, 0.64 mmol). Yield for Bocprotected intermediate 138 mg (72%). LC/MS method A: R_(t)=6.43 min.purity >90%. (M+H)⁺=448. Yield for final product (111 mg, 100%, 72%overall). LC/MS method A: R_(t)=4.03 min., (M+H)⁺=348.

Example 199: Synthesis of(S)-2-amino-N1,N-bis(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pentanediamide

(S)-2-amino-N1,N5-bis(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pentanediamidewas prepared according to the procedure of example 147 from2-amino-6-(trifluoromethoxy) benzimidazole (117 mg, 0.5 mmol) and N-Boc(S)-2-aminopentanedioic acid (62 mg, 0.25 mmol). Yield for Boc protectedintermediate 42 mg (25%). LC/MS method A: R_(t)=5.72 min., purity >90%,(M+H)⁺=679. Yield for final product (17 mg, 40%, 10% overall). LC/MSmethod A: R_(t)=4.99 min., (M+H)⁺=580.

Example 200: Synthesis of2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide

2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) wasprepared according to the procedure of example 147 from2-amino-6-(trifluoromethoxy) benzimidazole (117 mg, 0.5 mmol) and2-(dimethylamino)acetic acid (58 mg, 0.75 mmol). Yield=200 mg (93%).LC/MS method A: R_(f)=3.35 min., purity >90%, (M+H)⁺=320.

Example 201: Synthesis of1,3-bis(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)urea

A mixture of 2-amino-6-(trifluoromethoxy) benzimidazole (936 mg, 4.0mmol) and triphosgene (593 mg, 2.0 mmol) in chloroform (10 mL) washeated to 60° C. for 18 hours. The solid was filtered off (unreactedriluzole) and filtrate was diluted with ethyl acetate (50 ml), washedwith 1N HCl (25 ml), saturated aqueous NaHCO₃ (25 ml) and brine (25 ml),dried over MgSO₄ and concentrated to give the isocyanide intermediate.Yield=375 mg (36%). LC/MS method A: R_(t)=6.41 min., purity >90%,(M+H)⁺=261.19. A mixture of the isocyanide (26 mg, 0.1 mmol) and2-amino-6-(trifluoromethoxy) benzimidazole (23 mg, 0.1 mmol) in2-butanone (0.5 mL) was stirred at 60° C. for 72 hours. The mixture wasconcentrated and the residue was stirred in methylene chloride for 20minutes, the solid was collected, washed with methylene chloride anddried under vacuum. Yield=23 mg (46%). LC/MS method A: R_(t)=6.90 min.,(M+H)⁺=496.

Example 202: Synthesis of Benzyl2-(2-{[(tert-butoxy)carbonyl]amino}acetamido) acetate

A solution of (tert-butyloxycarbonyl)glycine (0.39 g, 2.3 mmol), glycinebenzyl ester hydrochloride (0.50 g, 2.5 mmol) and triethylamine (0.51 g,5.0 mmol, 0.70 ml) in N,N-dimethylformamide (10 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (0.95 g, 2.5 mmol) and stirred 18 hours. Themixture was diluted with ethyl acetate (75 ml) and washed with 1N HCl(50 ml), water (50 ml), 1M sodium carbonate solution (50 ml), water (50ml) and brine (25 ml). The organic phase was dried (MgSO₄) andevaporated to leave benzyl 2-(2-{[(tert-butoxy)carbonyl]amino}acetamido) acetate as a waxy solid (800 mg, 99%). LC/MS method A:R_(t)=4.30 min., (M+H)⁺=323. ¹H-NMR (CDCl₃): δ=7.36 (s, 5H), 6.55 (bs,1H), 5.20 (s, 2H), 5.09 (bs, 1H), 4.11 (d, J=5.2 Hz, 2H), 3.86 (d, J=5.8Hz, 2H), 1.46 (s, 9H).

Example 203: Synthesis of2-(2-{[(tert-Butoxy)carbonyl]amino}acetamido)acetic acid

Benzyl 2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)acetate (790 mg, 2.4mmol) was hydrogenated at one atmosphere hydrogen pressure over 10% Pd/C(100 mg) in methanol (25 ml) for 18 h. The catalyst was filtered overcelite, washed with methanol (2×5 ml) and the filtrate evaporated underreduced pressure to leave2-(2-([(tert-butoxy)carbonyl]amino)acetamido)acetic acid as a solid (555mg, 100%). ¹H-NMR (CD₃OD): δ=3.92 (s, 2H), 3.75 (s, 2H), 1.45 (s, 9H).

Example 204: Synthesis of2-Amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamide

A solution of2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride (40 mg, 0.11 mmol), (tert-butyloxycarbonyl)glycylglycine(28 mg, 0.12 mmol) and triethylamine (33 mg, 0.33 mmol, 46 μl) inN,N-dimethylformamide (1 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (44 mg, 0.12 mmol) and the mixture wasstirred for 18 hours. The mixture was then purified by RPHPLC without aworkup procedure (method B) and the product fractions were combined,treated with saturated aqueous sodium bicarbonate solution (50 ml) andextracted with ethyl acetate (2×25 ml). The combined organic phases werewashed with brine (2×25 ml), dried (MgSO₄) and evaporated under reducedpressure to leave a solid (34 mg, 60%). LC/MS method A: R_(t)=4.86 min.,(M+H)⁺=520.

The solid was dissolved in methylene chloride (1 ml) and trifluoroaceticacid (1 ml) and allowed to stand for 2 hours. The solvents wereevaporated and the residue was dissolved in water (25 ml) andlyophilized to leave2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamide as a light yellow powder trifluoroacetic acidsalt (40 mg, 60% over two steps). LC/MS method A: R_(t)=3.69 min.,(M+H)⁺=420. ¹H-NMR (CD₃OD): δ=7.84 (d, J=1.8 Hz, 1H), 3:1 conformers at7.78 and 7.80 (d, J=8.8 Hz, 1H), 7.35 (dd, J=8.8 Hz, J=1.8 Hz, 1H), 3:1conformers at 4.45 and 4.38 (s, 2H), 3:1 conformers at 4.28 and 4.15 (s,2H), 3.75 (s, 2H), 3:1 conformers at 3.20 and 3.02 (s, 3H).

Example 205: Synthesis of Benzyl2-{[(tert-butoxy)carbonyl](oxan-4-yl)amino}acetate

A solution of 4-aminotetrahydropyran (0.46 g, 4.6 mmol) intetrahydrofuran (10 ml) was treated with triethylamine (0.59 g, 5.8mmol, 0.80 ml) and bromobenzylacetate (1.3 g, 5.8 mmol, 0.91 ml) andstirred for 24 hours, tert-butyloxycarbonyl anhydride (1.0 g, 4.6 mmol)was added and the mixture stirred for 72 hours. The mixture was dilutedwith ethyl acetate (50 ml) and 1N HCl (50 ml) and separated. The organiclayer was washed with water (30 ml), dried (MgSO₄) and evaporated toleave benzyl 2-{[(tert-butoxy)carbonyl](oxan-4-yl)amino}acetate as asolid (0.80 g, 50%). LC/MS method A: R_(t)=5.43 min., (M+H)⁺=250(M+H)⁺−100, (t-butyloxcarbonyl)). ¹H-NMR (CDCl₃): δ=7.35 (s, 5H), 5.16(s, 2H), 4.25-4.40 (m, 1H), 3.90-4.01 (m, 2H), 3.84 (s, 2H), 3.44 (t,2H, J=11.7 Hz), 1.33-1.73 (m, 13H).

Example 206: Synthesis of2-{[(tert-Butoxy)carbonyl](oxan-4-yl)amino}acetic acid

A solution of 2-{[(tert-butoxy)carbonyl](oxan-4-yl)amino}acetate (0.80g, 2.3 mmol) was hydrogenated at 1 atmosphere hydrogen pressure over 5%Pd/C (100 mg) in methanol (25 ml) for 2 hours. The mixture was filteredover celite, washed with methanol (2×5 ml) and concentrated to yield2-{[(tert-butoxy)carbonyl](oxan-4-yl)amino}acetic acid as a solid (0.61g, 100%). ¹H-NMR (CDCl₃): δ=conformers at 4.25-4.40 and 3.60-3.80 (m,1H), 3.80-4.05 (m, 4H), 3.45 (t, J=14.3 Hz, 2H), 1.50-1.95 (m, 4H), 1.45(s, 9H).

Example 207: Synthesis of tert-ButylN-([methyl(([6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl)methyl)carbamoyl]methyl)-N-(oxan-4-yl)carbamate

A solution of 2-{[(tert-butoxy)carbonyl](oxan-4-yl)amino}acetic acid (52mg, 0.15 mmol),2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride (50 mg, 0.13 mmol) and N,N-diisopropylethylamine (50 mg,0.39 mmol, 70 μl) in N,N-dimethylformamide (1 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (57 mg, 0.15 mmol) and the mixture stirredfor 18 hours. The product mixture was purified by reversed phase HPLC(RPHPLC, method B) without a workup to yield 66 mg (93%) of tert-butylN-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-N-(oxan-4-yl)carbamateas a solid. LC/MS method A: R_(t)=5.46 min., (M+H)⁺=547.

Example 208: Synthesis ofN-Methyl-2-[(oxan-4-yl)amino]-N-(([6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoylmethyl)acetamide

A solution of tert-butylN-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-N-(oxan-4-yl)carbamate(66 mg) in 1,4-dioxane (2 ml) was treated with 4N HCl in 1,4-dioxane (2ml) and the mixture stirred for 2 hours. The product precipitated as afine white powder which was collected by filtration, washed with dioxaneand ether, and dried to yield 56 mg (83%) ofN-methyl-2-[(oxan-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamidedihydrochloride salt. LC/MS method A: R_(t)=3.89 min., (M+H)⁺=447.¹H-NMR (CD₃OD): δ=7.85 (d, J=1.5 Hz, 1H), 3:1 conformers at 7.81 and7.80 (d, J=9.1 Hz, 1H), 7.36 (dd, J=9.1 Hz and J=1.5 Hz, 1H), 4.44 (s,2H), 3:1 conformers at 4.24 and 4.10 (s, 2H), 4.02 (dd, J=12.0 Hz, J=6.5Hz, 2H), 3.35-3.50 (m, 3H), 3:1 conformers at 3.18 and 3.04 (s, 3H),2.20-2.10 (m, 2H), 1.70 (ddd, J=17.0, J=12.4 Hz, J=5.0 Hz, 21).

Example 209: Synthesis of tert-Butyl3-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}azetidine-1-carboxylate

Tert-Butyl 3-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}azetidine-1-carboxylate was prepared according to theprocedure for Example 205 from tert-butyl3-aminoazetidine-1-carboxylate. (0.82 g, 42%). LC/MS method A:R_(t)=6.08 min., (M+Na)⁺=423. ¹H-NMR (CDCl₃): δ=7.36 (s, 5H), 5.17 (s,2H), conformers at 4.90-4.50 and 4.35-4.50 (m, 1H), 3.80-4.20 (m, 6H),3.84 (s, 2H), 1.33-1.53 (m, 18H).

Example 210: Synthesis of2-{[(tert-Butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]azetidin-3-yl})amino}aceticacid

2-{[(tert-Butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]azetidin-3-yl})amino}aceticacid was prepared according to the procedure for Example 206 from 0.82 g(2.0 mmol) of tert-butyl3-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}azetidine-1-carboxylate(0.64 g, 97%). ¹H-NMR (CDCl₃): δ=conformers at 4.93-5.02 and 4.45-4.53(m, 1H), 3.83-4.22 (m, 6H), 1.44 (s, 18H).

Example 211: Synthesis of tert-Butyl3-{[(tert-butoxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino}azetidine-1-carboxylate

Tert-Butyl3-{[(tert-butoxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino}azetidine-1-carboxylatewas prepared according to the procedure for Example 207 from2-{[(tert-butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]azetidin-3-yl})amino}aceticacid and2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride (75 mg 94%). LC/MS method A: R_(t)=6.01 min.,(M+H)⁺=618. NMR??

Example 212: Synthesis of2-[(Azetidin-3-yl)amino]-N-methyl-N-(([6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoylmethyl)acetamide

2-[(Azetidin-3-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamidewas prepared according to the procedure for Example 208 from tert-butyl3-{[(tert-butoxy)carbonyl](([methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl))amino}azetidine-1-carboxylate (75 mg) to yield 43 mg(63%) of2-[(azetidin-3-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide as a white powder. LC/MS method A: ¹H-NMR (CD₃OD): δ=7.85 (d,J=1.5 Hz, 1H), 3:1 conformers at 7.81 and 7.80 (d, J=8.8 Hz, 1H), 7.35(dd, J=8.8 Hz and J=1.5 Hz, 1H), 4.20-4.60 (m, 9H), 3:1 conformers at3.21 and 3.18 (s, 3H).

Example 213: Synthesis of tert-Butyl4-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}piperidine-1-carboxylate

Tert-Butyl4-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}piperidine-1-carboxylatewas prepared according to the procedure for Example 205 from tert-butyl4-aminopiperidine-1-carboxylate. Left tert-butyl4-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}piperidine-1-carboxylate (1.3 g, 63%). LCMSmethod A: R_(t)=5.43 min. (M+Na)⁺=471. ¹H-NMR (CDCl₃): δ=7.36 (s, 5H),5.15 (s, 2H), 4.10-4.30 (m, 3H), conformers at 3.94 and 3.80 (s, 2H),2.65-2.80 (m, 2H), 1.70-1.78 (m, 2H), conformers at 1.35-1.45 (s, 18H).

Example 214: Synthesis of2-([(tert-Butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]piperidin-4-yl))amino}acetic acid

2-{[(tert-Butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]piperidin-4-yl))amino}acetic acid was prepared according to theprocedure for Example 206 from tert-butyl4-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}piperidine-1-carboxylate(1.3 g, 2.9 mmol) to provide2-{[(tert-butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]piperidin-4-yl})amino}aceticacid (1.0 g, 96%) as a solid. ¹H-NMR (CDCl₃): δ=4.10-4.32 (m, 3H),3.78-3.95 (m, 2H), 2.65-2.81 (m, 2H), 1.75 (d, J=10.3 Hz, 2H), 1.52 (bs,20H).

Example 215: Synthesis of tert-Butyl4-{[(tert-butoxy)carbonyl]({[methyl(([6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoylmethyl)carbamoyl]methyl)amino) piperidine-1-carboxylate

Tert-Butyl4-{[(tert-butoxy)carbonyl]({[methyl([6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbanoyl]methyl)amino}piperidine-1-carboxylate was prepared according to the procedure forExample 207 from2-{[(tert-butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]piperidin-4-yl}amino}aceticacid and2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride to yield 82 mg (98%) of tert-butyl4-{[(tert-butoxy)carbonyl]({[methyl([6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})aminopiperidine-1-carboxylate. LC/MS method A: R_(t)=6.20 min., (M+H)⁺=646.

Example 216: Synthesis ofN-Bethyl-2-[(piperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

N-Bethyl-2-[(piperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamidewas prepared according to the procedure for Example 208 from ten-butyl4-{[(tert-butoxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}amino}piperidine-1-carboxylate(82 mg) to yield 57 mg (79%) ofN-methyl-2-[(piperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamideas a white powder. LCJMS method A: R_(t)=3.47 min., (M+H)⁺=447. ¹H-NMR(CD₃OD): δ=7.85 (d, J=2.0 Hz, 1H), 3:1 conformers at 7.81 and 7.80 (d,J=8.8 Hz, 1H), 7.36 (dd, J=8.8 Hz and J=2.0 Hz, 1H), 3:1 conformers at4.45 and 4.47 (s, 2H), 3:1 conformers at 4.32 and 4.18 (s, 2H),3.50-3.61 (m, 3H), 3:1 conformers at 3.20 and 3.05 (s, 3H), 3.12 (ddd,J=13.2 Hz, J=13.2 Hz, J=3.0 Hz, 2H), 2.42 (d, J=13.2 Hz, 2H), 1.95 (ddd,J=20.1 Hz, J=13.2 Hz, J=4.1 Hz, 2H).

Example 217: Synthesis of2-[N-Methyl-2-(morpholin-4-yl)acetamido]-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamide

A solution of 2-(morpholin-4-yl)acetic acid (50 mg, 0.34 mmol),2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride (106 mg, 0.31 mmol) and DIPEA (88 mg, 0.64 mmol, 122 μl)in N, N-dimethyl formamide (2 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (129 mg, 0.34 mmol) and stirred for 72hours. The mixture was purified by RPHPLC (method B) and the productfractions were combined and lyophilized to leave2-[N-methyl-2-(morpholin-4-yl)acetamido]-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamideas a white powder (92 mg, 54%). LC/MS method A: R_(t)=3.87 min.,(M+H)⁺=433. ¹H-NMR (CD₃OD): δ=7.85 (d, J=1.2 Hz, 1H), 3:1 conformers at7.81 and 7.99 (d, J=9.0 Hz, 1H), 7.36 (dd, J=9.0 Hz, J=1.2 Hz, 1H), 3:1conformers at 4.44 and 4.41 (s, 2H), 3:1 conformers at 4.43 and 4.25 (s,2H), 3.80-4.10 (m, 4H), 3.20-3.60 (m, 4H), 3:1 conformers at 3.16 and3.05 (s, 3H).

Example 218: Synthesis of2-[N-Methyl-2-(piperazin-1-yl)acetamido]-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamide

A solution of 2-{4-[(tert-butoxy)carbonyl]piperazin-1-yl}acetic acid (41mg, 0.17 mmol),2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride (50 mg, 0.15 mmol) and N,N-diisopropylethylamine (22 mg,0.17 mmol, 30 μl) in N,N-dimethylformamide (1 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (65 mg, 0.17 mmol) and stirred 3 hours. Themixture was diluted with ethyl acetate (25 ml) and washed with water (25ml) and brine (25 ml). The organic phase was dried (MgSO₄) andevaporated. The crude product was purified by RPHPLC (method B) and theproduct fractions were combined, treated with saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate (2×50 ml). Thecombined organic phases were washed with brine (25 ml) and dried(MgSO₄). The solvents were evaporated to leave a colorless glassy solidwhich was dissolved in dichloromethane and trifluoroacetic acid (1:1, 3ml) and allowed to stand for 2 h. The solvents were evaporated and theresidue was dissolved in water (10 ml) and lyophilized to leave2-[N-methyl-2-(piperazin-1-yl)acetamido]-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamideas a white powder (74 mg, 75%). LC/MS method A: R_(t)=3.54 min.,(M+H)⁺=432. ¹H-NMR (CD₃OD): δ=7.86 (d, J=10.3 Hz, 1H), 1:1 conformers at7.81 and 7.99 (d, J=8.8 Hz, 1H), 7.36 (m, 1H), 1:1 conformers at 4.43and 4.38 (s, 2H), 1:1 conformers at 3.71 and 3.40 (s, 2H), 3.35-3.39 (m,2H), 1:1 conformers at 3.20 and 3.08 (s, 3H), 3.00-3.10 (m, 4H),2.68-2.75 (m, 2H).

Example 219: Synthesis of Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}propanamido]acetate

Benzyl 2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}propanamido]acetat wasprepared according to the procedure for benzyl2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)acetate from(tert-butyloxycarbonyl)alanine to leave benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}propanamido]acetate as a solid.LC/MS method A: R_(t)=5.38 min. (M+H)⁺=337. ¹H-NMR (CDCl₃): δ=7.36 (s,5H), 6.63 (bs, 1H), 5.20 (s, 2H), 4.94 (bs, 1H), 4.21 (q, J=7.0 Hz, 1H),4.09 (ABq, J=5.3 Hz, 2H), 1.45 (s, 9H), 1.37 (d, J=7.0 Hz, 3H).

Example 220: Synthesis of2-[(2S)-2-{[(tert-Butoxy)carbonyl]amino)propanamido]acetic acid

Benzyl 2-[(2S)-2-{[(tert-butoxy)carbonyl]amino} propanamido]acetat wasprepared according to the procedure for benzyl2-(2-([(tert-butoxy)carbonyl]amino}acetamido)acetate from Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl] amino}propanamido]acetate to provide2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}propanamido] acetic acid as asolid. ¹H-NMR (CDCl₃): δ=4.10 (q, J=7.3 Hz, 1H), 3.90 (ABq, J=17.9 Hz,2H), 1.44 (s, 9H), 1.32 (d, J=7.0 Hz, 3H).

Example 221: Synthesis of(2S)-2-Amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl)propanamide

(2S)-2-Amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}propanamidewas prepared according to the procedure for2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamidefrom (tert-butyloxycarbonyl)alanylglycineto provide(2S)-2-amino-N-{[methyl(([6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}propanamide.LC/MS method A: R_(t)=3.72 min., (M+H)⁺=434. ¹H-NMR (CD₃OD): δ=7.84 (d,J=1.8 Hz, 1H), 3:1 conformers at 7.78 and 7.80 (d, J=8.7 Hz, 1H), 7.35(dd, J=8.7 Hz, J=1.8 Hz, 1H), 3:1 conformers at 4.46 and 4.38 (s, 2H),4.26 (ABq, J=17.3 Hz, 2H), 4.00 (q, J=7.0 Hz, 1H), 3:1 conformers at3.20 and 3.02 (s, 3H), 1.52 (d, J=7.0 Hz, 3H).

Example 222: Synthesis of Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenyl propanamido]acetate

Benzyl 2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropanamido]acetate was prepared according to the procedure for benzyl2-(2-{[(tert-butoxy)carbonyl]amino} acetamido)acetate from(tert-butyloxycarbonyl)phenylalanine to provide benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropanamido]acetate.LC/MS method A: R_(t)=5.38 min., (M+Na)⁺=435. ¹H-NMR (CDCl₃):δ=7.18-7.40 (m, 10H), 6.37 (bs, 1H), 5.17 (s, 2H), 4.92 (bs, 1H), 4.03(ABq, J=18.5 Hz, J=5.6 Hz, 1H), (ABq, J=18.4 Hz, J=5.0 Hz, 1H), 3.10(doublet of ABq, J=14.0 Hz, J=6.7 Hz, J=4.7 Hz, 2H), 1.40 (s, 9H).

Example 223: Synthesis of2-[(2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-phenylpropanamido]acetic acid

2-[(2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-phenylpropanamido]acetic acidwas prepared according to the procedure for2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)acetic acid from Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropanamido]acetate toprovide2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropanamido]acetic acidas a solid. ¹H-NMR (CD₃OD): δ=7.18-7.30 (m, 5H), 4.34 (dd, J=9.7 Hz,J=5.3 Hz, 1H), 3.91 (s, 2H), 3.17 (dd, J=13.7 Hz, J=4.7 Hz, 1H), 2.80(dd, J=13.7 Hz, J=9.7 Hz, 1H), 1.34 (s, 9H).

Example 224: Synthesis of(2S)-2-Amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-3-phenylpropanamide

(2S)-2-Amino-N-[methyl([6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoylmethyl)carbamoyl]methyl)-3-phenylpropanamide was prepared according tothe procedure for2-amino-N-[methyl([6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl)methyl)carbamoyl]methylacetamide from (tert-butyloxycarbonyl)phenylalanylglycine. LC/MS methodA: R_(t)=4.19 min., (M+H)⁺=510. ¹H-NMR (CD₃OD): δ=7.85 (bs, 1H), 3:1conformers at 7.81 and 7.79 (d, J=7.4 Hz, J=8.8 Hz, 1H), 7.27-7.40 (m,6H), 3:1 conformers at 4.45 and 4.38 (s, 2H), 3:1 conformers at 4.22 and4.10 (ABq, J=17.3 Hz, J=15.0 Hz, 2H), 4.15 (obscured dd, 1H), 3.12(obscured dd, 1H), 3:1 conformers at 3.20 and 3.02 (s, 3H), 3.04(obscured dd, 1H).

Example 225: Synthesis of Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methyl butanamido]acetate

A solution of (tert-butyloxycarbonyl)valine succinate ester (0.71 g, 2.3mmol) and glycine benzyl ester hydrochloride (0.50 g, 2.5 mmol) inN,N-dimethylformamide (10 ml) was treated with triethylamine (0.51 g,5.0 mmol, 0.70 ml) and stirred 18 hours. A white precipitate formed. Themixture was diluted with ethyl acetate (75 ml) and washed with 1N HCl(50 ml), water (50 ml) and brine (25 ml). The organic phase was dried(MgSO₄) and evaporated to leave benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]acetate as awaxy solid (829 mg, 100%). LC/MS method A: R_(t)=5.03 min., (M+Na)⁺=387.¹H-NMR (CDC₃): δ=7.36 (s, 51H), 6.45 (bs, 1H), 5.19 (s, 2H), 5.00 (bs,1H), 4.10 (dd, J=5.3 Hz, J=2.6 Hz, 2H), 3.00 (dd, J=7.2 Hz, J=5.6 Hz,1H), 2.15-2.25 (m, 1H), 1.45 (s, 9H), 0.98 (d, J=6.8 Hz, 3H), 0.92 (d,J=7.1 Hz, 3H).

Example 226: Synthesis of2-[(2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-methyl butanamido]acetic acid

2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]acetate(0.82 g, 2.2 mmol) was hydrogenolyzed (1 atmosphere hydrogen pressure)in methanol (25 ml) over 5% Pd/C (100 mg) for 18 hours. The catalyst wasfiltered through a bed of celite, washed with methanol (2×5 ml) and thefiltrate was evaporated under reduced pressure to afford2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]acetic acidas a solid (636 mg, 100%). ¹H-NMR (CD₃OD): δ=8.20 (bs, 1H), 3.80-4.03(m, 3H), 2.00-2.15 (m, 1H), 1.44 (s, 9H), 0.97 (d, J=6.8 Hz, 3H), 0.93(d, J=6.8 Hz, 3H).

Example 227: Synthesis of(2S)-2-Amino-3-methyl-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}butanamide

(2S)-2-Amino-3-methyl-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}butanamidewas prepared according to the procedure for2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl} acetamide from (tert-butyloxycarbonyl)valylglycine.LC/MS method A: R_(t)=3.91 min., (M+H)⁺=462. ¹H-NMR (CD₃OD): δ=7.84 (d,J=1.2 Hz, 1H), 3:1 conformers at 7.79 and 7.80 (d, J=8.8 Hz, 1H), 7.35(dd, J=8.8 Hz, J=1.2 Hz, 1H), 3:1 conformers at 4.46 and 4.39 (s, 2H),3:1 conformers at 4.28 and 4.15 (ABq, J=10.0 Hz, J=4.7 Hz, 2H), 3:1conformers at 4.15 and 3.71 (d, J=5.9 Hz, 1H), 3:1 conformers at 3.20and 3.02 (s, 3H), 2.15-2.25 (m, 1H), 1.07 (d, J=6.8 Hz, 3H), 1.06 (d,J=7.0 Hz, 3H).

Example 228: Synthesis of Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]acetate

Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]acetate wasprepared according to the procedure for benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]acetate from(tert-butyloxycarbonyl)leucine succinate ester to provide benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]acetate asan oil. LC/MS method A: R_(t)=5.32 min., (M+Na)⁺=401. ¹H-NMR (CDCl₃):δ=7.36 (s, 5H), 6.61 (bs, 1H), 5.18 (s, 2H), 4.84 (bd, J=8.5 Hz, 1H),4.15 (bs, 1H), 4.08 (d, J=5.2 Hz, 2H), 1.65-1.75 (m, 3H), 1.44 (s, 9H),0.95 (d, J=6.1 Hz, 3H), 0.92 (d, J=6.1 Hz, 3H).

Example 229: Synthesis of2-[(2S)-2-([(tert-Butoxy)carbonyl]amino)-4-methyl pentanamido]aceticacid

2-[(2S)-2-{[(tert-Butoxy)carbonyl]amino}-4-methyl pentanamido]aceticacid was prepared according to the procedure for2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]acetic acidfrom Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]acetate toprovide2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]acetic acidas a solid. ¹H-NMR (CD₃OD): δ=4.11 (dd, J=10.4 Hz, J=5.0 Hz, 1H), 3.90(ABq, J=17.9 Hz, 2H), 1.50-1.80 (m, 3H), 1.44 (s, 9H), 0.95 (d, J=6.4Hz, 3H), 0.93 (d, J=6.2 Hz, 3H).

Example 230: Synthesis of(2S)-2-Amino-4-methyl-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl)pentanamide

(2S)-2-Amino-4-methyl-N-([methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}pentanamidewas prepared according to the procedure for2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamidefrom (tert-butyloxycarbonyl)leucylglycine. LC/MS method A: R_(t)=4.09min., (M+H)⁺=476. ¹H-NMR (CD₃OD): δ=7.84 (d, J=2.1 Hz, 1H), 3:1conformers at 7.79 and 7.77 (d, J=8.8 Hz, J=7.2 Hz, 1H), 7.35 (dm, J=7.8Hz, 1H), 3:1 conformers at 4.46 and 4.38 (s, 2H), 3:1 conformers at 4.26and 4.13 (ABq, J=15.2 Hz, J=9.1 Hz, 2H), 3.93 (dd, J=7.6 Hz, J=6.2 Hz,1H), 3:1 conformers at 3.20 and 3.02 (s, 3H), 1.65-1.80 (m, 3H), 1.01(d, J=5.6 Hz, 3H), 0.99 (d, J=5.0 Hz, 3H).

Example 231: Synthesis of Benzyl 2-[(oxetan-3-yl)amino]acetate

A solution of 4-aminooxetane (300 ng, 4.1 mmol) and benzyl2-bromoacetate (1.3 g, 5.8 mmol, 0.91 ml) in acetonitrile (10 ml) wasstirred 72 hours. The mixture was diluted with 1N HCl (50 ml) andextracted with ethyl acetate (50 ml). The aqueous layer was neutralized(pH=9) with solid sodium carbonate and extracted with ethyl acetate(2×50 ml). The combined organic layers were washed with brine, dried(MgSO₄) and evaporated under reduced pressure to leave benzyl2-[(oxetan-3-yl)amino]acetate as an oil (160 mg, 17%). ¹H-NMR (CDCl₃):δ=7.36 (m, 5H), 5.16 (s, 2H), 4.76 (t, J=7.0 Hz, 2H), 4.48 (t, J=6.4 Hz,2H), 3.92-4.01 (m, 11H), 3.45 (s, 2H).

Example 232: Synthesis of Benzyl2-{[(tert-butoxy)carbonyl](oxetan-3-yl)amino}acetate

A solution of 2-[(oxetan-3-yl)amino]acetate (15 mg, 0.66 mmol) inmethylene chloride (5 ml) was treated with tert-butyloxycarbonylanhydride (168 mg, 0.79 mmol) and stirred 18 hours. The solvents wereevaporated and the residue was purified by chromatography on silica geleluted with a gradient of ethyl acetate in hexanes (10% to 20% to 40%)to leave benzyl 2-{[(tert-butoxy)carbonyl](oxetan-3-yl)amino}acetate asa colorless oil (200 mg, 90%). LC/MS method A: R_(t)=5.13 min. ¹H-NMR(CDCl₃): δ=7.36 (bs, 5H), 1:1 conformers at 5.22-5.35 and 4.90-5.00 (m,1H), 5.18 (s, 2H), 4.58-4.85 (m, 4H), 4.12 (s, 2H), 1:1 conformers at1.45 and 1.37 (s, 9H).

Example 233: Synthesis of2-{[(tert-Butoxy)carbonyl](oxetan-3-yl)amino)acetic acid

2-([(tert-butoxy)carbonyl](oxetan-3-yl)amino}acetate (195 mg, 0.58 mmol)was hydrogenated (1 atmosphere hydrogen pressure) over 10% Pd/C (30 mg)in methanol (5 ml) for 18 hours. The catalyst was filtered and washedwith methanol (2×5 ml) and the filtrate was evaporated to leave2-{[(tert-butoxy)carbonyl](oxetan-3-yl)amino}acetic acid as a whitesolid (135 mg, 100%). ¹H-NMR (CDCl₃): δ=1:1 conformers at 5.22-5.35 and4.90-5.05 (m, 1H), 4.60-4.90 (m, 4H), 4.12 (s, 2H), 1.45 (s, 9H).

Example 234: Synthesis ofN-Methyl-2-[(oxetan-3-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

A solution of 2-{[(tert-butoxy)carbonyl](oxetan-3-yl)amino}acetic acid(30 mg, 0.13 mmol),2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride (40 mg, 0.12 mmol) and triethylamine (26 mg, 0.26 mmol,36 μl) in N,N-dimethylformamide (1 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (49 mg, 0.13 mmol) and stirred 18 hours. Theproduct was purified by reversed phase HPLC (method B) and the productfractions were combined, treated with saturated sodium bicarbonatesolution (50 ml) and extracted with ethyl acetate (2×50 ml). Thecombined organic phases were washed with brine (25 ml), dried (MgSO₄)and evaporated to a thick gum (47 mg, 76%). This was dissolved in 4N HClin 1,4-dioxane (3 ml) and stirred for 2 hours. The solvents wereevaporated and the residue was dissolved in water (8 ml) andacetonitrile (2 ml) and lyophilized to leave a white powder (36 mg, 56%over two steps). LC/MS method A: R_(t)=4.23 min., (M+H)⁺=419. ¹H-NMR(CD₃OD): δ=7.85 (bs, 1H), 3:1 conformers at 7.81 and 7.79 (d, J=7.9 Hz,J=8.8 Hz, 1H), 7.35 (dm, J=7.9 Hz, 1H), 4.00-4.50 (m, 7H), 3:1conformers at 3.20 and 3.02 (s, 3H).

Example 235: Synthesis of (2,2,2-Trifluoro-ethylamino)-acetic acid ethylester

A flask was charged with 2,2,2-Trifluoroethylamine hydrochloride (2.81g, 20.7 mmol) and potassium iodide (340 mg, 2.07 mmol). DIEA (14.5 mL)was added to the flask and the mixture was stirred for 5 minutes beforeadding ethyl bromoacetate (3.46 g, 20.7 mmol, 2.3 mL). The slurry wasstirred overnight at room temperature. The slurry was diluted withdiethyl ether (75 mL) and stirred for 1 hour. The reaction mixture wasfiltered and the filtrate was concentrated in vacuo. The crude residuewas dissolved in methylene chloride (30 mL) and extracted into 1N HCl(2×30 mL). The aqueous layer was neutralized with sat. aqueous NaHCO₃and the product was extracted with methylene chloride (3×30 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo to provide (2,2,2-Trifluoro-ethylamino)-aceticacid ethyl ester as a brown oil. ¹H NMR (300 MHz, CDCl₃) δ=4.27-4.14 (m,2H), 3.56-3.48 (m, 2H), 3.31-3.17 (m, 2H), 1.29 (t, J=7.0 Hz, 3H)

Example 236: Synthesis of[(2-Chloro-acetyl)-(2,2,2-trifluoro-ethyl)-amino]-acetic add ethyl ester

Chloroacetyl chloride (358 mg, 3.17 mmol, 252 μL) was added dropwise toa solution of (2,2,2-trifluoro-ethylamino)-acetic acid ethyl ester (489mg, 2.64 mmol) and diisopropylethylamine (751 mg, 5.81 mmol, 1.01 mL) indichloromethane (13 mL) at 0° C., keeping the temperature <5° C. duringthe addition. The mixture was stirred for 30 minutes then quenched with1N HCl (13 mL). The layers were separated and the aqueous layer wasextracted with methylene chloride (2×13 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo togive 672 mg (97%) of ethyl[(2-Chloro-acetyl)-(2,2,2-trifluoro-ethyl)-amino]-acetate as a brownoil. ¹H NMR (300 MHz, CDCl₃) δ=4.45-3.99 (m, 8H), 1.37-1.24 (m, 3H)

Example 237: Synthesis of[(2-tert-Butylamino-acetyl)-(22,2-trifluoro-ethyl)-amino]-acetic acidethyl ester

tert-Butylamine (296 mg, 4.05 mmol, 426 μL) was added to a solution of[(2-chloro-acetyl)-(2,2,2-trifluoro-ethyl)-amino]-acetic acid ethylester (265 mg, 1.01 mmol) and diisopropylethylamine (131 mg, 1.01 mmol,176 μL) in dichloromethane (5 mL) and the reaction was stirredovernight. The product was extracted into 1N HCl (2×10 mL). The aqueouslayer was neutralized with sat. aqueous NaHCO₃ and the product wasextracted with methylene chloride (3×10 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo to130 mg (43%) of[(2-tert-butylamino-acetyl)-(2,2,2-trifluoro-ethyl)-amino]-acetic acidethyl ester as a brown oil. ¹H NMR (300 MHz, CDCl₃) δ=4.22 (d, J=17.6Hz, 4H), 4.17-4.02 (m, 2H), 3.56-3.35 (m, 2H), 1.36-1.24 (m, 3H), 1.10(d, J=5.0 Hz, 9H)

Example 238: Synthesis of2-tert-Butylamino-N-(2,2,2-trifluoro-ethyl)-N-[(6-trifluoromethoxy-benzothiazol-2-ylcarbamoyl)-methyl]-acetamide

Sodium ethoxide (45 mg, 0.65 mmol) was added to a stirred solution of2-amino-6-(trifluoromethoxy)benzothiazole (102 mg, 0.44 mmol) in ethanol(2.5 mL) at room temperature. After stirring for 10 minutes, a solutionof [(2-tert-butylamino-acetyl)-(2,2,2-trifluoro-ethyl)-amino]-aceticacid ethyl ester (130 mg, 0.44 mmol,) in ethanol (1 mL) was added. Themixture was stirred overnight. The reaction was quenched with water (500μL) then concentrated to dryness in vacuo. The residue was diluted withN,N-dimethylformamide and purified by prep HPLC (method B). The purifiedproduct was freeze dried from dioxane to obtain 97 mg (37%) of thetrifluoroacetic acid salt of2-tert-butylamino-N-(2,2,2-trifluoro-ethyl)-N-[(6-trifluoromethoxy-benzothiazol-2-ylcarbamoyl)-methyl]-acetamideas a white powder. LC/MS method A: R_(t)=4.42 min., (M+H)⁺=487. 1H NMR(300 MHz, DMSO-d6) δ=12.91-12.56 (m, 1H), 9.08-8.63 (m, 2H), 8.32-7.97(m, 1H), 7.93-7.75 (m, 1H), 7.54-7.25 (m, 1H), 4.69-4.52 (m, 2H),4.49-4.32 (m, 2H), 4.13-3.95 (m, 2H), 1.38-1.19 (m, 9H).

Example 239: Synthesis of Benzyl2-[{(tert-butoxy)carbonyl](cyclohexyl)amino}acetate

A solution of benzyl 2-bromoacetate (1.3 g, 5.8 mmol), cyclohexylamine(456.5 mg, 4.6 mmol) and triethylamine (0.59 g, 5.8 mmol) intetrahydrofuran (10 mL) was stirred 18 h. Di-tert-butyl dicarbonate (1g, 4.6 mmol) was added and the reaction stirred for 24 hours. Ethylacetate (100 ml) was added and the mixture was washed with water (2×50ml), 1N HCl (50 ml), and brine (25 ml). The organic solution was driedover sodium sulfate and evaporated to give a crude product. Purificationby silica gel chromatography afforded benzyl2-{[(tert-butoxy)carbonyl](cyclohexyl)amino}acetate as a colorless oil(1.03 g, 65%). LC/MS method A: R_(t)=6.44 min., (M+H)⁺−100(t-butoxycarbonyl)=248. ¹H NMR (300 MHz, CDCl₃): δ 7.40-7.24 (m, 5H),5.15 (s, 2H), 4.03-3.95 (m, 1H), 3.82 (s, 2H), 1.77-1.74 (m, 4H),1.47-1.44 (m, 2H), 1.34 (s, 9H), 1.31-1.17 (m, 4H).

Example 240: Synthesis of2-{[(tert-Butoxy)carbonyl](cyclohexyl)amino)acetic acid

Benzyl 2-{[(tert-butoxy)carbonyl](cyclohexyl)amino}acetate (1.035 g,2.98 mmol) in methanol (20 mL) was hydrogenated (1 atmosphere H₂pressure) over Pd/C (100 mg) for 18 hours. The mixture was filteredthrough celite and the filtrate was evaporated to give2-([(tert-butoxy)carbonyl](cyclohexyl)amino}acetic acid as a white solid(0.75 g, 98%). LC/MS method A: R_(t)=5.20 min., (M+Na)⁺=280. ¹H NMR (300MHz, CDCl₃): δ 4.03-3.84 (m, 3H), 1.81-1.61 (m, 4H), 1.44 (s, 9H),1.43-1.07 (m, 6H).

Example 241: Synthesis of2-(Cyclohexylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (50 mg, 0.13 mmol),2-{[(tert-butoxy)carbonyl](cyclohexyl)amino}acetic acid (38.6 mg, 0.15mmol) and N,N-diisopropylethylamine (50 mg, 0.39 mmol, 70 ul) inN,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 57 mg, 0.15 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified via RPHPLC(method B) to give a light yellow foamy solid (LC/MS method A;R_(t)=6.07 min., (M+Na)⁺=566.6). The solid was dissolved in 4N HCl in1,4-dioxane. The mixture stirred 18 h and the white precipitate wasfiltered on a glass frit (medium), washed with 1,4-dioxane and ether anddried under vacuum to leave2-(cyclohexylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamideas a white crystalline solid (49.1 mg, 70%). LC/MS method A: R_(t)=4.00min., (M+H)⁺=445. ¹H NMR (300 MHz, CD₃OD): δ 7.96-7.73 (m, 2H), 7.36 (d,J=8.80 Hz, 1H), 4.43 (s, 2H), 4.20 (s, 2H), 3.17 (s, 3H), 3.04 (m, 1H),2.13 (m, 2H), 1.89 (m, 2H), 1.72 (d, J=11.73 Hz, 1H), 1.49-1.20 (m, 5H).

Example 242: Synthesis of Benzyl2-{[(tert-butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino}acetate

A mixture of benzyl 2-bromoacetate (1.3 g, 5.8 mmol),4-Amino-1-methanesulfonylpiperidine (820 mg, 4.6 mmol) and triethylamine(0.59 g, 5.8 mmol) in tetrahydrofuran (10 mL) was stirred for 18 hours.Di-tert-butyl dicarbonate (1 g, 4.6 mmol) was added and the mixturestirred for another 20 hours. Ethyl acetate (100 ml) was added and themixture was washed with water (2×50 ml), 1N HCl (50 ml), and brine (25ml). The organic solution was dried over sodium sulfate and evaporatedto give a crude product which was purified by chromatography on silicagel to give benzyl 2-{[(tert-butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino}acetate as a colorless oil (1.56 g, 79.5%). LC/MSmethod A: R_(t)=5.24 min., (M+H)⁺−100 (t-butyloxycarbonyl)=327. ¹H NMR(300 MHz, CDCl₃): δ 7.36 (s, 5H), 5.16 (s, 2H), 3.97-3.87 (m, 1H), 3.82(s, 2H), 2.78 (s, 3H), 2.77-2.68 (m, 2H), 1.89-1.85 (m, 2H), 1.71-1.61(m, 2H), 1.48-1.45 (m, 2H), 1.35 (s, 9H).

Example 243: Synthesis of2-{[(tert-Butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino}aceticacid

Benzyl2-{[(tert-butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino}acetate(1.56 g, 3.66 mmol) was hydrogenated (1 atmosphere hydrogen pressure) inmethanol (20 mL) over Pd/C (100 mg) for 20 hours. The mixture wasfiltered through celite and evaporated to give2-{[(tert-butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino}aceticacid as a white solid (0.97 g, 79%). LC/MS method A: R_(t)=3.37 min.,(M+Na)⁺=359. ¹H NMR (300 MHz, CDCl₃): δ 3.88-3.84 (m, 1H), 3.81 (s, 2H),2.80 (s, 3H), 2.76-2.71 (m, 2H), 1.90-1.87 (m, 2H), 1.64-1.60 (m, 2H),1.59-1.45 (m, 2H), 1.43 (s, 9H).

Example 244: Synthesis of2-[(1-Methanesulfonylpiperidin-4-yl)amino]-N-methyl-N-{([6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (50 mg, 0.13 mmol),2-[(tert-butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino)aceticacid (50.46 mg, 0.15 mmol) and N,N-diisopropylethylamine (50 mg, 0.39mmol, 70 ul) in N,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 57 mg, 0.15 mmol) and the reactionmixture stirred for 18 hours. The crude mixture was purified by RPHPLC(method B) and the product fractions were evaporated to give a lightyellow foamy solid (LC/MS, method A; R_(t)=5.12 min., (M+Na)⁺=646). Thesolid was dissolved in 4N HCl in 1,4-dioxane. The mixture stirredovernight and the white precipitate was filtered on a glass frit(medium), washed with 1,4-dioxane and ether and dried under vacuum toleave 61.1 mg (59%) of2-[(1-methanesulfonylpiperidin-4-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamideas a white crystalline solid. LC/MS method A: R_(t)=3.72 min.,(M+H)⁺=524. ¹H NMR (300 MHz, CD₃OD): δ 7.95-7.70 (m, 2H), 7.36 (d,J=8.21 Hz, 1H), 4.44 (s, 2H), 4.34-4.06 (m, 2H), 3.87 (d, J=12.31 Hz,2H), 3.36 (m, 1H), 3.18 (s, 3H), 2.87 (s, 3H), 2.81 (m, 2H), 2.25 (d,J=9.97 Hz, 2H), 1.88-1.55 (m, 2H)

Example 245: Synthesis of tert-Butyl N-(2-amino-2-methylpropyl)carbamate

A mixture of 2-methylpropane-1,2-diamine (1.1 g, 12.5 mmol) indichloromethane (10 mL) was cooled to 0° C., Di-tert-butyl dicarbonate(2.7 g, 12.5 mmol) was added and the mixture was stirred 20 hours. Thesolvent was evaporated to give tert-butylN-(2-amino-2-methylpropyl)carbamate as a white solid (2.4 g, 100%) whichwas used directly for the next step without characterization. LC/MSmethod A: R_(t)=3.70 min., (M+H)⁺=327. ¹H NMR (300 MHz, CDCl₃): δ7.38-7.27 (m, 5H), 5.17 (s, 2H), 3.41 (s, 2H), 3.01-2.99 (d, J=5.8 Hz,2H), 1.44 (s, 9H), 1.24 (s, 6H).

Example 246: Synthesis of Benzyl2-{[(tert-butoxy)carbonyl](1-([(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino)acetate

A mixture of benzyl 2-bromoacetate (3.04 g, 13 mmol), tert-butylN-(2-amino-2-methylpropyl)carbamate (2.5 g, 13 mmol), triethylamine (1.7g, 16 mmol) in tetrahydrofuran (15 mL) was stirred 18 h.Di-tert-butyldicarbonate (2.8 g, 13 mmol) was added and the mixturestirred for another 24 hours. Ethyl acetate (100 ml) was added and themixture was washed with water (2×50 ml), 1N HCl (50 ml), and brine (25ml). The organic solution was dried over sodium sulfate and evaporatedto give a crude product which was purified by silica gel chromatographyelute with a hexanes/ethyl acetate gradient to give benzyl2-{[(tert-butoxy)carbonyl](1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino}acetateas a colorless oil (1.27 g, 23%) along with amine starting material(0.74 g, 17%). LC/MS method A: R_(t)=6.26 min., (M+Na)⁺=459. ¹H NMR (300MHz, CD₃OD): δ 7.40-7.31 (m, 5H), 5.19 (s, 2H), 4.07 (s, 2H), 3.46 (s,2H), 1.42 (s, 9H), 1.35 (s, 6H), 1.32 (s, 9H).

Example 247: Synthesis of2-{[(tert-Butoxy)carbonyl](1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino}aceticacid

Benzyl2-{[(tert-butoxy)carbonyl](1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino}acetate(178 mg, 0.41 mmol) in methanol (20 mL) was hydrogenated (1 atmospherehydrogen pressure) over Pd/C (50 mg) for 20 hours. The mixture wasfiltered through celite and evaporated to give2-{[(tert-butoxy)carbonyl](1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino}aceticacid as a colorless oil (161 mg, 100%). LC/MS method A: R_(t)=4.7 min.,(M+Na)⁺=369.

Example 248: Synthesis of2-[(1-Amino-2-methylpropan-2-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (51.68 mg, 0.14 mmol),2-{[(tert-butoxy)carbonyl](1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino}aceticacid (52 mg, 0.15 mmol) and N,N-diisopropylethylamine (53 mg, 0.41 mmol,70 ul) in N,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 57 mg, 0.15 mmol) and the reactionmixture stirred for 18 hours. The crude product was purified by RPHPLC(method B) to give a light yellow foamy solid (LC/MS method A, R_(t)=6.0min. (M+H)⁺=634.33). This was dissolved in 4N HCl in 1,4-dioxane. Themixture was stirred 20 hours and the white precipitate was filtered on aglass frit (medium), washed with 1,4-dioxane and ether and dried undervacuum to leave 49 mg (72%) of2-[(1-amino-2-methylpropan-2-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamideas a white crystalline solid. LC/MS method A: R_(t)=3.27 min.,(M+H)⁺=434. ¹H NMR (300 MHz, CD₃OD): δ 7.93-7.73 (m, 2H), 7.36 (d,J=8.21 Hz, 1H), 4.55-4.42 (m, 2H), 4.36-4.16 (m, 2H), 3.37 (m, 2H), 3.22(s, 3H), 1.60-1.49 (m, 6H).

Example 249: Synthesis of tert-Butyl4-([2-(benzyloxy)-2-oxoethyl](methyl)amino) piperidine-1-carboxylate

A mixture of benzyl 2-bromoacetate (1.3 g, 5.8 mmol),1-(tert-butyloxcarbonyl)-4-(methylamino)piperidine (1.24 g, 5.8 mmol)and triethylamine (0.59 g, 5.8 mmol) in tetrahydrofuran (10 mL) wasstirred overnight. Water (50 ml) was added followed by ethyl acetateextraction 2×100 ml). The organic solution was dried over sodium sulfateand evaporated to give a crude product which was purified bychromatography on silica gel using a gradient of ethyl acetate inhexanes to give tert-butyl4-{[2-(benzyloxy)-2-oxoethyl](methyl)amino}piperidine-1-carboxylate as acolorless oil (1.87 g, 84%). LC/MS method A: R_(t)=3.76 min.,(M+Na)⁺=385. ¹H NMR (300 MHz, CDCl₃): δ 7.34 (m, 5H), 5.14 (s, 2H),4.11-4.09 (m, 2H), 3.37 (s, 2H), 2.68-2.60 (m, 3H), 2.40 (s, 3H),1.79-1.74 (m, 2H), 1.43 (s, 9H), 1.36-1.31 (m, 2H).

Example 250: Synthesis of2-({1-[(tert-Butoxy)carbonyl]piperidin-4-yl}(methyl)amino) acetic acid

tert-Butyl4-{[2-(benzyloxy)-2-oxoethyl](methyl)amino}piperidine-1-carboxylate(1.87 g, 5.17 mmol) in methanol (20 mL) was hydrogenated (one atmospherehydrogen pressure) over Pd/C (150 mg) for 18 hours. The mixture wasfiltered through celite and the filtrate was evaporated to give2-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)acetic acid asa colorless oil (1.365 g, 97%). LC/MS method A: R_(t)=2.62 min.,(M+H)⁺=273. ¹H NMR (300 MHz, CDCl₃): δ 4.25 (m, 2H), 3.45 (s, 2H),3.38-3.30 (m, 1H), 2.74 (m, 5H), 2.04-2.00 (m, 2H), 1.57-1.52 (m, 2H),1.48 (s, 9H).

Example 251: Synthesis of2-{N-Methyl-2-[methyl(piperidin-4-yl)amino]acetamido}-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (55.5 ing, 0.15 mmol),2-{(1-[(tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)acetic acid(44 mg, 0.16 mmol) and N,N-diisopropylethylamine (57 mg, 0.44 mmol, 73ul) in N,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 61.6 mg, 0.15 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified by RPHPLC(method B) to give tert-butyl4-[methyl({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino]piperidine-1-carboxylate as a white foamy solid. R_(t)=4.19 min,(M+H)⁺=560.20).

tert-Butyl4-[methyl({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino]piperidine-1-carboxylate was dissolved in 4N HClin 1,4-dioxane. The mixture stirred overnight and the white precipitatewas filtered on a glass frit (medium), washed with 1,4-dioxane and etherand dried under vacuum to leave2-{N-methyl-2-[methyl(piperidin-4-yl)amino]acetamido}-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamideas a white solid (61 mg, 73%). LC/MS method A: R_(t)=3.45 min.,(M+H)⁺=460. ¹H NMR (300 MHz, CD₃OD): δ 7.93-7.71 (m, 2H), 7.37 (d,J=8.80 H, 1H), 4.47 (m, 2H), 4.09 (m, 2H), 3.19 (s, 3H), 3.06 (m, 1H),2.37 (m, 1H), 2.02 (m, 6H), 1.33-1.16 (m, 4H).

Example 252: Synthesis of Benzyl2-{[(tert-butoxy)carbonyl](1-methylpiperidin-4-yl) amino}acetate

A mixture of benzyl 2-bromoacetate (1.3 g, 5.8 mmol),4-amino-1-methylpiperidine (2.5 g, 13 mmol) and triethylamine (0.59 g,5.8 mmol) in tetrahydrofuran (10 mL) was stirred 20 hours. D-tert-butyldicarbonate (1 g, 4.6 mmol) was added and stirring continued for 20hours. Ethyl acetate (100 ml) was added and the mixture was washed withwater (2×50 ml), 1N HCl (50 ml), and brine (25 ml). The organic solutionwas dried over sodium sulfate and evaporated to give a crude productwhich was purified by chromatography on silica gel using a gradient ofethyl acetate in hexanes to give benzyl2-{[(tert-butoxy)carbonyl](1-methylpiperidin-4-yl)amino}acetate as acolorless oil (0.116 g, 7%). LC/MS method A: R_(t)=3.74 min.,(M+H)⁺=363. ¹H NMR (300 MHz, CDCl₃): δ 7.34 (m, 5H), 5.14 (s, 2H),4.10-3.96 (m, 1H), 3.83 (s, 1H), 2.88-2.84 (m, 2H), 2.25 (s, 3H),2.06-1.99 (m, 2H), 1.74-1.71 (m, 2H), 1.59-1.55 (m, 1H), 1.47 (s, 3H),1.36 (s, 6H).

Example 253: Synthesis of2-{[(tert-Butoxy)carbonyl](1-methylpiperidin-4-yl)amino} acetic acid

HO N A solution of benzyl2-{[(tert-butoxy)carbonyl](1-methylpiperidin-4-yl)amino}acetate (116.2mg, 0.32 mmol) in methanol (20 mL) was hydrogenated (1 atmospherehydrogen pressure) over 10% Pd/C (100 mg) for 20 hours. The mixture wasfiltered through celite and the filtrate was evaporated to give2-{[(tert-butoxy)carbonyl](1-methylpiperidin-4-yl)amino}acetic acid as acolorless oil (89 mg, 100%). LC/MS method A: R_(t)=2.36 min.,(M+H)⁺=273.

Example 254: Synthesis ofN-Methyl-2-[(1-methylpiperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl)methyl)acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (71.8 mg, 0.19 mmol),2-([(tert-butoxy)carbonyl](1-methylpiperidin-4-yl)amino}acetic acid(56.9 mg, 0.21 mmol) and N,N-diisopropylethylamine (73.6 mg, 0.57 mmol,94 ul) in N,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 79.5 mg, 0.21 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified by RPHPLC(method B) to give tert-butylN-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-N-(1-methylpiperidin-4-yl)carbamate a lightyellow foamy solid (138 mg). LC/MS (method A): R_(t)=4.02 min.,(M+H)⁺=560.

tert-ButylN-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-N-(1-methylpiperidin-4-yl)carbamate was dissolved in4N HCl in 1,4-dioxane. The mixture stirred 18 hours and the whiteprecipitate was filtered on a glass frit (medium), washed with1,4-dioxane and ether and dried under vacuum to leaveN-methyl-2-[(1-methylpiperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamideas a white powder (55 mg, 51%). LC/MS method A: R_(t)=3.26 min.,(M+H)⁺=460. ¹H NMR (300 MHz, CD₃OD): δ 7.72-7.94 (m, 2H), 7.36 (d,J=8.80 Hz, 1H), 4.47 (m, 2H), 4.31-4.16 (m, 2H), 3.49-3.44 (m, 1H), 3.19(s, 3H), 2.89 (s, 3H), 2.46-2.41 (m, 2H), 2.06-2.02 (m, 2H), 1.30-1.44(m, 4H).

Example 255: Synthesis of tert-Butyl N-(1-acetylpiperidin-4-yl)carbamate

A mixture of tert-butyl piperidin-4-ylcarbamate (3.69 g, 18.4 mmol) andtriethylamine (5.57 g, 55 mmol) in tetrahydrofuran (10 mL) was cooled to0° C. Acetic anhydride (2.25 g, 22 mmol) was added and stirred for 18hours. Ethyl acetate (100 ml) was added and the mixture was washed withwater (2×50 ml), 1N HCl (50 ml), and brine (25 ml). The organic solutionwas dried over sodium sulfate and evaporated to give tert-butylN-(1-acetylpiperidin-4-yl)carbamate as a beige solid (4.7 g, 100%).LC/MS method A: R_(t)=3.39 min., (M+H)⁺=243. ¹H NMR (300 MHz, CDCl₃): δ4.47 (d, J=11.4 Hz, 2H), 3.77-3.75 (m, 2H), 3.15-3.06 (m, 1H), 2.80-2.66(m, 2H), 2.07 (s, 3H), 1.99-1.89 (m, 2H), 1.42 (s, 9H).

Example 256: Synthesis of N-(1-Acetylpiperidin-4-yl)amine

A solution of tert-butyl N-(1-acetylpiperidin-4-yl)carbamate (4.0 g, 17mmol) stood in 1:1 trifluoroacetic acid-methylene chloride (50 ml) for 2hours and was then evaporated to dryness to leaveN-(1-acetylpiperidin-4-yl)amine as a solid (4.4 g, 100%) which was usedwithout characterization for the next step.

Example 257: Synthesis of Benzyl2-[(1-acetylpiperidin-4-yl)amino]acetate

A mixture of benzyl 2-bromoacetate (1.3 g, 5.8 mmol),1-(4-aminopiperidin-1-yl)ethan-1-one (1.8 g, 10 mmol), and triethylamine(3 g, 30 mmol) in tetrahydrofuran (10 mL) was stirred 18 hours.Saturated sodium bicarbonate solution (50 ml) was added followed byaddition of ethyl acetate (50 ml). The organic layer was washed withwater (2×50 ml) and brine (25 ml). The organic solution was dried oversodium sulfate and evaporated to give benzyl2-[(1-acetylpiperidin-4-yl)amino]acetate as a colorless oil (1.56 g,54%). LC/MS method A: R_(t)=2.76 min., (M+H)⁺=291.

Example 258: Synthesis of Benzyl2-[(1-acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino]acetate

A mixture of benzyl 2-[(1-acetylpiperidin-4-yl)amino]acetate (1.56 g,5.4 mmol) and triethylamine (1.09 g, 10.8 mmol) in tetrahydrofuran (10mL) was cooled to 0° C. Di-tert-butyl dicarbonate (1.17 g, 5.4 mmol) wasadded and stirred for 20 hours. Ethyl acetate (100 ml) was added and themixture was washed with water (2×50 ml), 1N HCl (50 ml), and brine (25ml). The organic solution was dried over sodium sulfate and evaporatedto give a crude product which was purified by silica gel chromatographyeluted with a gradient of ethyl acetate in hexanes to leave benzyl2-[(1-acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino]acetate as acolorless oil (0.8 g, 38%). LC/MS method A: R_(t)=4.73 min., (M+H)⁺=391.

Example 259: Synthesis of2-[(1-Acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino] acetic acid

A solution of benzyl2-[(1-acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino]acetate (0.8 g,2 mmol) in methanol (50 mL) was hydrogenated (1 atmosphere hydrogenpressure) over 10% Pd/C (100 mg) for 20 hours. The mixture was filteredthrough celite and the filtrate was evaporated to give2-[(1-acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino]acetic acid asan oil (550 mg, 92%). LC/MS method A: R_(t)=3.15 min., (M+H)⁺=301.

Example 260: Synthesis of2-[(1-Acetylpiperidin-4-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (66.8 mg, 0.18 mmol), 2-[(1l-acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino]acetic acid (58.4mg, 0.19 mmol) and N,N-diisopropylethylamine (69 mg, 0.53 mmol, 88 ul)in N,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 73.8 mg, 0.19 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified by RPHPLC(method B) to give tert-butylN-(1-acetylpiperidin-4-yl)-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}carbamate as a light yellow foamy solid (LC/MSmethod A: R_(t)=4.74 min., (M+H)⁺=588), tert-ButylN-(1-acetylpiperidin-4-yl)-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}carbamatewas dissolved in 4N HCl in 1,4-dioxane. The mixture stirred overnightand the white precipitate was filtered on a glass frit (medium), washedwith 1,4-dioxane and ether and dried under vacuum to leave2-[(1-acetylpiperidin-4-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide (68 mg, 68.5%) as a white solid. LC/MS method A: R_(t)=3.52min., (M+H)⁺=488. ¹H NMR (300 MHz, CD₃OD): δ 7.88-7.78 (m, 2H),7.38-7.35 (m, 1H), 4.68-4.65 (m, 1H), 4.44 (s, 2H), 4.27-4.12 (m, 2H),3.19 (s, 3H), 2.71-2.63 (m, 1H), 2.23-2.20 (m, 1H), 2.11 (s, 3H),1.65-1.51 (m, 2H), 1.39-1.34 (m, 4H).

Example 261: Synthesis of tert-Butyl4-{[2-(benzyloxy)-2-oxoethyl]amino}-4-methyl piperidine-1-carboxylate

A mixture of 4-methylpiperidin-4-amine (1 g, 8.76 mmol) indichloromethane (20 mL) was cooled to 0° C., Di-tert-butyl dicarbonate(1.9 g, 8.76 mmol) was added and the mixture was stirred 20 h. Thesolvent was evaporated to give a crude product to which was addedtetrahydrofuran (20 mL), followed by addition of triethylamine (3 mL, 22mmol) and benzyl 2-bromoacetate (2 g, 8.76 mmol). The mixture wasstirred 20 h. Ethyl acetate (100 ml) was added and the mixture waswashed with saturated sodium bicarbonate solution (50 ml), and brine (25ml). The organic solution was dried over sodium sulfate and evaporatedto give a crude product which was purified by RPHPLC (method B) to givetert-butyl4-{[2-(benzyloxy)-2-oxoethyl]amino)-4-methylpiperidine-1-carboxylate asa light yellowish oil (0.55 g, 17.3%). LC/MS method A: R_(t)=3.71 min.,(M+H)⁺=363.

Example 262: Synthesis of tert-Butyl4-([2-(benzyloxy)-2-oxoethyl][(benzyloxy)carbonyl]amino}-4-methylpiperidine-1-carboxylate

To a solution of tert-butyl4-{[2-(benzyloxy)-2-oxoethyl]amino}-4-methylpiperidine-1-carboxylate(0.51 g, 1.4 mmol) in dichloromethane (5 mL) at 0° C. was addedN,N-diisopropylethylamine (0.7 mL, 4.2 mmol), followed by Benzylchloroformate (0.29 g, 1.69 mmol). The reaction mixture was stirred at0° C. and naturally warmed to room temperature overnight. MoreN,N-diisopropylethylamine (0.7 mL, 4.2 mmol) and benzyl chloroformate(0.29 g, 1.69 mmol) was added and the reaction was stirred for 24 hours.The reaction mixture was diluted with dichloromethane (50 ml) and washedwith saturated sodium bicarbonate (50 ml) solution and brine (50 ml).The organic solution was dried over sodium sulfate and evaporated togive a crude product which was purified by RPHPLC (method B) to givetert-butyl4-{[2-(benzyloxy)-2-oxoethyl][(benzyloxy)carbonyl]amino}-4-methylpiperidine-1-carboxylate (256 mg, 37%). LC/MS method A: R_(t)=6.34 min.,(M+Na)⁺=519.

Example 263: Synthesis of2-{[(Benzyloxy)carbonyl]({1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino}acetic acid

To a solution of tert-butyl4-{[2-(benzyloxy)-2-oxoethyl][(benzyloxy)carbonyl]amino}-4-methylpiperidine-1-carboxylate(256 mg, 0.50 mmol) in dioxane (5 mL) was added 2N LiOH (1 mL). Themixture was stirred for 20 h, 1N HC was added slowly till the pH was 7.Extracted with ethyl acetate (100 ml) and the organic solution was driedover sodium sulfate and evaporated to give2-{[(benzyloxy)carbonyl]({1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino}aceticacid as a colorless oil (226 mg, 100%). Used for the next step withoutfurther purification. LC/MS method A: R_(t)=5.02 min., (M+Na)⁺=429.

Example 264: Synthesis of tert-Butyl4-{[(benzyloxy)carbonyl]({[(2-ethoxy-2-oxoethyl)(methyl)carbamoyl]methyl))amino}-4-methylpiperidine-1-carboxylate

To a solution of Sarcosine ethyl ester hydrochloride (94 mg, 0.61 mmol),2-([(benzyloxy)carbonyl]((1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino)aceticacid (226 mg, 0.56 mmol) and N,N-diisopropylethylamine (217 mg, 1.68mmol, 300 ul) in N,N-dimethylformamide (4 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 233 mg, 0.61 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified by RPHPLC(method B) to give tert-butyl4-{[(benzyloxy)carbonyl]({[(2-ethoxy-2-oxoethyl)(methyl)carbamoyl]methyl})amino}-4-methylpiperidine-1-carboxylate as a colorless oil (218 mg, 77%). LC/MS methodA: R_(t)=5.5 min., (M+H)⁺=506.

Example 265: Synthesis of2-(2-{[(Benzyloxy)carbonyl]({1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino}-N-methylacetamido)aceticacid

To a solution of tert-butyl4-([(benzyloxy)carbonyl](([(2-ethoxy-2-oxoethyl)(methyl)carbamoyl]methyl)amino)-4-methylpiperidine-1-carboxylate (142 mg, 0.28mmol) in dioxane (1 mL) was added 2N NaOH. The mixture was stirred 20 h,1N HCl was added slowly until th pH reached 7. The product was extractedwith ethyl acetate (100 ml) and the organic solution was dried oversodium sulfate and evaporated to give a crude product which was purifiedby silica gel chromatography to give2-(2-{[(benzyloxy)carbonyl]({1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino}-N-methylacetamido)acetic acid as a colorless oil(100 mg, 75%). LC/MS method A: R_(t)=4.72 min., (M+Na)⁺=500.

Example 266: Synthesis of tert-Butyl4-([(benzyloxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl)amino-4-methylpiperidine-1-carboxylate

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (59 mg, 0.252 mmol),2-(2-{[(benzyloxy)carbonyl]({1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino)-N-methylacetamido)aceticacid (100 mg, 0.21 mmol) and N,N-diisopropylethylamine (81.4 mg, 0.63mmol, 104 ul) in N,N-ditnethylformamide (2 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluoro phosphate (HATU, 95.8 mg, 0.252 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified by RPHPLC(method B) to give tert-butyl4-([(benzyloxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbanoyl]methyl})amino}-4-methylpiperidine-1-carboxylateas a white solid (114 mg, 78%). LC/MS method A: R_(t)=6.13 min.,(M+H)⁺=694. ¹H NMR (300 MHz, CD₃OD): δ 7.84-7.77 (m, 2H), 7.35-7.27 (m,6H), 5.06 (s, 2H), 4.39 (s, 2H), 4.32-4.28 (m, 2H), 3.71-3.65 (m, 2H),3.24-3.18 (m, 2H), 3.13 (s, 3H), 2.15-2.12 (m, 2H), 1.93-1.89 (m, 2H),1.48 (s, 3H), 1.41 (s, 9H).

Example 267: Synthesis of tert-Butyl4-methyl-4-({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}amino)piperidine-1-carboxylate

A solution of tert-butyl4-{[(benzyloxy)carbonyl]({[methyl(([6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl)amino}-4-methylpiperidine-1-carboxylate(114 mg, 2 mmol) in methanol (20 mL) was hydrogenated (1 atmospherehydrogen pressure) over 10% Pd/C (100 mg) for 20 hours. The mixture wasfiltered through celite and the filtrate was evaporated to giveten-butyl4-methyl-4-({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}amino)piperidine-1-carboxylate as a colorlessoil (100 mg, 100%). LC/MS method A: R_(t)=4.22 min., (M+H)⁺=560.

Example 268: Synthesis ofN-Methyl-2-[(4-methylpiperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

To a solution of tert-butyl4-methyl-4-({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}amino)piperidine-1-carboxylate (100 mg, 0.179 mmol) in dioxane (1 mL)was added 4N HCl in 1,4-dioxane (2 mL). The mixture stirred overnightand the white precipitate was filtered, washed with 1,4-dioxane andether and dried under vacuum to leave 22 mg (22%) ofN-methyl-2-[(4-methylpiperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide as a white powder. LC/MS method A: R_(t)=3.28 min.,(M+H)⁺=460. ¹H NMR (300 MHz, CD₃OD): δ 7.73-7.91 (m, 2H), 7.36 (d,J=8.50 Hz, 1H), 4.45-4.51 (m, 2H), 3.48-3.52 (m, 2H), 3.23 (s, 3H),2.07-2.38 (m, 6H), 1.45-1.64 (m, 5H).

TABLE 1 Non-limiting exemplary compounds of the disclosure. EntryStructure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

TABLE 2 Further non-limiting exemplary compounds of the disclosure.Entry Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

Formulations

The present invention also relates to compositions or formulations whichcomprise the riluzole prodrug agents according to the present invention.In general, the compositions of the present invention comprise aneffective amount of one or more riluzole prodrug agents and saltsthereof according to the present invention which are effective and oneor more excipients.

For the purposes of the present invention the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent invention and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present invention have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability. The formulation can be used for once-a-day or multipletimes per day dosage.

The present teachings also provide pharmaceutical compositions thatinclude at least one compound described herein and one or morepharmaceutically acceptable carriers, excipients, or diluents. Examplesof such carriers are well known to those skilled in the art and can beprepared in accordance with acceptable pharmaceutical procedures, suchas, for example, those described in Remington's Pharmaceutical Sciences,17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton,Pa. (1985), the entire disclosure of which is incorporated by referenceherein for all purposes. As used herein, “pharmaceutically acceptable”refers to a substance that is acceptable for use in pharmaceuticalapplications from a toxicological perspective and does not adverselyinteract with the active ingredient. Accordingly, pharmaceuticallyacceptable carriers are those that are compatible with the otheringredients in the formulation and are biologically acceptable.Supplementary active ingredients can also be incorporated into thepharmaceutical compositions.

Compounds of the present teachings can be administered orally,parenterally or as orally dissolvable tablets (“ODT's”) or sublingualpreparations, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich can also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents, or encapsulating materials. The compoundscan be formulated in conventional manner, for example, in a mannersimilar to that used for known prodrug agents. Oral formulationscontaining a compound disclosed herein can comprise any conventionallyused oral form, including tablets, capsules, buccal forms, ODTs or othersublingual formulations, troches, lozenges and oral liquids, suspensionsor solutions. In powders, the carrier can be a finely divided solid,which is an admixture with a finely divided compound. In tablets, acompound disclosed herein can be mixed with a carrier having thenecessary compression properties in suitable proportions and compactedin the shape and size desired. The powders and tablets can contain up to99% of the compound. Capsules can contain mixtures of one or morecompound(s) disclosed herein with inert filler(s) and/or diluent(s) suchas pharmaceutically acceptable starches (e.g., corn, potato or tapiocastarch), sugars, artificial sweetening agents, powdered celluloses(e.g., crystalline and microcrystalline celluloses), flours, gelatins,gums, and the like.

Useful tablet formulations can be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, microcrystalline cellulose, sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodiumcitrate, complex silicates, calcium carbonate, glycine, sucrose,sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,mannitol, sodium chloride, low melting waxes, and ion exchange resins.Surface modifying agents include nonionic and anionic surface modifyingagents. Representative examples of surface modifying agents include, butare not limited to, poloxamer 188, benzalkonium chloride, calciumstearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitanesters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,magnesium aluminum silicate, and triethanolamine. Oral formulationsherein can utilize standard delay or time-release formulations to alterthe absorption of the compound(s). The oral formulation can also consistof administering a compound disclosed herein in water or fruit juice,containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions,emulsions, syrups, elixirs, and for inhaled delivery. A compound of thepresent teachings can be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, or amixture of both, or a pharmaceutically acceptable oils or fats. Theliquid carrier can contain other suitable pharmaceutical additives suchas solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, and osmo-regulators. Examples ofliquid carriers for oral and parenteral administration include, but arenot limited to, water (particularly containing additives as describedherein, e.g., cellulose derivatives such as a sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols andpolyhydric alcohols, e.g., glycols) and their derivatives, and oils(e.g., fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can be an oily ester such as ethyl oleateand isopropyl myristate. Sterile liquid carriers are used in sterileliquid form compositions for parenteral administration. The liquidcarrier for pressurized compositions can be halogenated hydrocarbon orother pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions orsuspensions, can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Compositions for oral administration can bein either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, forexample, as tablets, capsules, powders, solutions, suspensions,emulsions, granules, or suppositories. In such form, the pharmaceuticalcomposition can be sub-divided in unit dose(s) containing appropriatequantities of the compound. The unit dosage forms can be packagedcompositions, for example, packeted powders, vials, ampoules, prefilledsyringes or sachets containing liquids. Alternatively, the unit dosageform can be a capsule or tablet itself, or it can be the appropriatenumber of any such compositions in package form. Such unit dosage formcan contain from about 1 mg/kg of compound to about 500 mg/kg ofcompound, and can be given in a single dose or in two or more doses.Such doses can be administered in any manner useful in directing thecompound(s) to the recipient's bloodstream, including orally, viaimplants, parenterally (including intravenous, intraperitoneal andsubcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particulardisease state or disorder, it is understood that an effective dosage canvary depending upon the particular compound utilized, the mode ofadministration, and severity of the condition being treated, as well asthe various physical factors related to the individual being treated. Intherapeutic applications, a compound of the present teachings can beprovided to a patient already suffering from a disease in an amountsufficient to cure or at least partially ameliorate the symptoms of thedisease and its complications. The dosage to be used in the treatment ofa specific individual typically must be subjectively determined by theattending physician. The variables involved include the specificcondition and its state as well as the size, age and response pattern ofthe patient.

In some cases it may be desirable to administer a compound directly tothe airways of the patient, using devices such as, but not limited to,metered dose inhalers, breath-operated inhalers, multidose dry-powderinhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosoldispensers, and aerosol nebulizers. For administration by intranasal orintrabronchial inhalation, the compounds of the present teachings can beformulated into a liquid composition, a solid composition, or an aerosolcomposition. The liquid composition can include, by way of illustration,one or more compounds of the present teachings dissolved, partiallydissolved, or suspended in one or more pharmaceutically acceptablesolvents and can be administered by, for example, a pump or asqueeze-actuated nebulized spray dispenser. The solvents can be, forexample, isotonic saline or bacteriostatic water. The solid compositioncan be, by way of illustration, a powder preparation including one ormore compounds of the present teachings intermixed with lactose or otherinert powders that are acceptable for intrabronchial use, and can beadministered by, for example, an aerosol dispenser or a device thatbreaks or punctures a capsule encasing the solid composition anddelivers the solid composition for inhalation. The aerosol compositioncan include, by way of illustration, one or more compounds of thepresent teachings, propellants, surfactants, and co-solvents, and can beadministered by, for example, a metered device. The propellants can be achlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or otherpropellants that are physiologically and environmentally acceptable.

Compounds described herein can be administered parenterally orintraperitoneally. Solutions or suspensions of these compounds or apharmaceutically acceptable salts, hydrates, or esters thereof can beprepared in water suitably mixed with a surfactant such ashydroxyl-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof in oils. Underordinary conditions of storage and use, these preparations typicallycontain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection can include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In some embodiments, the form can sterile and its viscositypermits it to flow through a syringe. The form preferably is stableunder the conditions of manufacture and storage and can be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

Compounds described herein can be administered transdermally, i.e.,administered across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministration can be carried out using the compounds of the presentteachings including pharmaceutically acceptable salts, hydrates, oresters thereof, in lotions, creams, foams, patches, suspensions,solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of atransdermal patch containing a compound, such as a compound disclosedherein, and a carrier that can be inert to the compound, can benon-toxic to the skin, and can allow delivery of the compound forsystemic absorption into the blood stream via the skin. The carrier cantake any number of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments can be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the compound can also be suitable. Avariety of occlusive devices can be used to release the compound intothe blood stream, such as a semi-permeable membrane covering a reservoircontaining the compound with or without a carrier, or a matrixcontaining the compound. Other occlusive devices are known in theliterature.

Compounds described herein can be administered rectally or vaginally inthe form of a conventional suppository. Suppository formulations can bemade from traditional materials, including cocoa butter, with or withoutthe addition of waxes to alter the suppository's melting point, andglycerin. Water-soluble suppository bases, such as polyethylene glycolsof various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds ofthe present teachings into host cells either in vitro or in vivo. Lipidformulations and nanocapsules can be prepared by methods known in theart.

To increase the effectiveness of compounds of the present teachings, itcan be desirable to combine a compound with other agents effective inthe treatment of the target disease. For example, other active compounds(i.e., other active ingredients or agents) effective in treating thetarget disease can be administered with compounds of the presentteachings. The other agents can be administered at the same time or atdifferent times than the compounds disclosed herein.

Compounds of the present teachings can be useful for the treatment orinhibition of a pathological condition or disorder in a mammal, forexample, a human subject. The present teachings accordingly providemethods of treating or inhibiting a pathological condition or disorderby providing to a mammal a compound of the present teachings includingits pharmaceutically acceptable salt) or a pharmaceutical compositionthat includes one or more compounds of the present teachings incombination or association with pharmaceutically acceptable carriers.Compounds of the present teachings can be administered alone or incombination with other therapeutically effective compounds or therapiesfor the treatment or inhibition of the pathological condition ordisorder.

Non-limiting examples of compositions according to the present inventioninclude from about 0.001 mg to about 1000 mg of one or more riluzoleprodrug according to the present invention and one or more excipients;from about 0.01 mg to about 100 mg of one or more riluzole prodrugaccording to the present invention and one or more excipients; and fromabout 0.1 mg to about 10 mg of one or more riluzole prodrug according tothe present invention; and one or more excipients.

Procedures

The following procedures can be utilized in evaluating and selectingcompounds as riluzole prodrugs.

Stability in Simulated Gastric Fluid (SGF) and Simulated IntestinalFluid (SIF).

Procedure from Baudy et al. (J. Med. Chem. 2009, 52, 771-778) used. Thephysiological stability of prodrugs was determined by examining thestability of the compound in SGF, and SIF at 37° C. The compounds wereprepared in a 9:1 mixture of the appropriate test component (SGF, SIF)and acetonitrile to a final concentration of 0.01 mg/mL. The sampleswere thoroughly mixed and maintained at 37° C. Each sample was injectedconsecutively onto an Agilent 1100 system (Luna C18, 3 μm, 50 mm×3 mm; 1mL/min; mobile phase of 0.1% trifluoroacetic acid in water/0.1%trifluoroacetic acid in acetonitrile) after a 3 h period. The percentremaining of prodrug was calculated by comparing the area of prodrugcompound versus riluzole generated. The identities of the parentcompounds and conversion products were confirmed by LC/MS.

Plasma Stability:

Assessment of plasma stability was carried out by individual incubationsof drug candidates in fresh mouse or human control plasma at aconcentration of 1 uM for 1 hour at 37° C. After which, the samples werede-proteinized by addition of 2 volumes of acetonitrile containing 0.1%formic acid and internal standard, vortex mixed for 2 minutes andcentrifuged at 4000 rpm for 10 minutes to pellet precipitated protein.The resulting supernatant containing the drug candidates was diluted5-fold with water containing 0.1% formic acid and submitted to LC-MS/MSanalysis. All determinations were done in triplicate. Plasma stabilitywas expressed as percent of control remaining.

Metabolic Stability:

In vitro metabolic stability was determined in pooled mouse or humanliver microsomes (BD Gentest) at a protein concentration of 0.5 mg/mL inreaction buffer (100 mM KH₂PO₄, pH 7.4 and 12 mM MgCl₂). Each drugcandidate was added to a final concentration of 1 uM. This mixture waspre-warmed to 37° C. for 10 minutes prior to starting the reaction withthe addition of β-Nicotinamide adenine dinucleotide 2′-phosphate reduced(NADPH) to a final concentration of 1 mM. A parallel incubation lackingNADPH served as the control. After incubation for 30 min at 37° C., thereactions were quenched by the addition of acetonitrile containing 0.1%formic acid and internal standard, vortex mixed for 2 minutes andcentrifuged at 4000 rpm for 10 minutes to pellet the precipitatedprotein. The resulting supernatant containing the drug candidate and itspotential metabolites was diluted 5-fold with water containing 0.1%formic acid and submitted to LC-MS/MS analysis. Metabolic stability wasexpressed as percent of control remaining.

LC-MS/MS Analysis:

An aliquot from each incubation was analyzed by LC-MS/MS with SRMdetection in the positive ionization mode using an ABSciex API 5500QTrap Mass Spectrometer interfaced via the ABSciex Turbo V IonSpraysource (ESI) to an Eksigent ExpressHT LC system. Best peak shape andseparation from interfering matrix species was afforded by an Eksigent3C18-CL-300, 3μ, 50×1 mm column. A fast gradient, from 15 to 85% organicin 2.5 minutes, with run time of 5.0 minutes, and flow rate of 50 uL/minwas utilized. Peak areas were integrated using MultiQuant v2.0 softwarefrom ABSciex.

Rat Pharmacokinetic Studies of the Compounds of the Disclosure:

The pharmacokinetics of the compounds of the disclosure and releasedriluzole were evaluated following either a single intravenous or oraladministration of the prodrug to fasted male Sprague-Dawley rats atsuggested dose levels (mg/Kg body weight). Blood samples were collectedat pre-determined time points including a 0 h time point and usuallybetween 7 and 8 additional time points not exceeding a 24 h period.Plasma concentrations of the prodrug and riluzole were determined byLC-MS/MS and pharmacokinetic parameters were determined using WinNonlin(v6.3).

Plasma samples were extracted and analyzed using the methods describedin Plasma Sample Extraction and Analysis. Average plasma concentrationsfor selected examples and plasma pharmacokinetic parameters are shown inTables 2. All data are expressed as ng/mL of the free base. Samples thatwere below the limit of quantification (0.5 ng/mL) were not used in thecalculation of averages.

Pharmacokinetic parameters were calculated from the time course of theplasmaconcentrations. Pharmacokinetic parameters were determined withPhoenix Winnonlin (v6.3) software using a non-compartmental model. Themaximum plasma concentration (Cmax) and time to the maximum plasmaconcentration (Tmax) of the compound of the disclosure were observedfrom the data. The area under the concentration-time curve (AUC) of thecompound of the disclosure was calculated using the trapezoidal formulawith calculation to the last quantifiable data point, and to infinity ifapplicable. Plasma half-life (t1/2) was calculated from 0.693/slope ofthe terminal elimination phase. Mean residence time, MRT, was calculatedby dividing the area under the moment curve (AUMC) by the AUC. Anysamples below the limit of quantitation (0.5 ng/mL) were treated as zerofor pharmacokinetic data analysis.

Plasma Sample Extraction and Analysis:

Analytical stock solutions (1.00 mg/mL of the free compound of thedisclosure) were prepared in DMSO. Standards were prepared in dilutedmatrix containing 1 part 10% formic acid and 9 parts Sprague-Dawley ratplasma containing sodium heparin as the anticoagulant (pre-diluted with1 part of 0.5M citric acid and 9 parts whole blood). Working solutionswere prepared in 50:50 acetonitrilc:water. Working solutions were thenadded to plasma to make calibration standards to final concentrations of1000, 500, 100, 50, 10, 5, 1, and 0.5 ng/mL. Standards contained boththe test article and riluzole. Standards were treated identically to thestudy samples.

Sample Extraction:

Plasma samples were extracted via acetonitrile precipitation on a TomtecQuadra 96-Model 320 liquid handling system in a 96-well plate format.

Step 1

-   -   1) Standards: Add 10 μL of appropriate working solution to 50 μL        of blank matrix in a 96-well plate.    -   2) Blanks: Add 10 μL 50:50 acetonitrile:water to 50 μL of blank        matrix in a 96-well plate.    -   3) Samples: Add 10 μL 50:50 acetonitrile:water to 50 μL of study        sample in a 96-well plate.    -   4) Cap and mix.        Step 2: Using the Tomtec, add 50 μL of sample to 150 μL of        acetonitrile (containing 100 ng/mL propranolol as an internal        standard) that has been pre-loaded onto a Sirocco Protein        Precipitation plate (Waters Corp.)        Step 3: Using the Tomtec, mix the samples via air aspiration        Step 4: Apply vacuum and collect filtrates into clean        polypropylene 96-well plate. Cap for analysis.

HPLC Conditions: Instrument: Waters Acquity UPLC Column: Waters AcquityBEH C18, 100×2.1 mm id, 1.7 μm

Mobile Phase Buffer: 40 mM ammonium formate, pH 3.5Aqueous Reservoir (A): 10% buffer, 90% waterOrganic Reservoir (B): 10% buffer, 90% acetonitrile

Gradient Program:

Time Grad. (min) Curve % A % B 0.00 6 90 10 3.75 6 0 100 4.00 6 90 105.00 6 90 10

Flow Rate: 400 μL/min Injection Volume: 5 μL Run Time: 5.0 min ColumnTemperature: 40° C. Sample Temperature: 8° C.

Strong Autosampler Wash: 1:1:1(v:v:v) water:methanol:isopropanol with0.2% formic acidWeak Autosampler Wash: 4 mM ammonium formate

Mass Spectrometer Conditions Instrument: PE Sciex API4000 Interface:Electrospray (“Turbo Ion Spray”) Mode: Multiple Reaction Monitoring(MRM) Gases: CUR 30, CAD 10, GS1 50, GS2 50 Source Temperature: 550° C.

Polarity: positive

Pharmacokinetic data for various examples via intravenous administrationis shown in Table 3. Table 4 shows pharmacokinetic data for Example 125via oral administration. FIG. 1 shows the time-concentration curves forExample 125 and released riluzole via both intravenous and oraladministration. These data demonstrate that the compounds of thedisclosure in Table 3 are converted to riluzole when givenintravenously. These data further demonstrate that the prodrug Example125 is converted to Riluzole with moderate to long half life duringintravenous administration and the prodrug Example 125 is converted toRiluzole with long half life, high oral bioavailability during oraladministration. Table 5 shows pharmacokinetic data for Example 204 viaoral administration. FIG. 3 shows the time-concentration curves forExample 204 and released riluzole via both intravenous and oraladministration. Table 6 shows pharmacokinetic data for Example 216 viaoral administration. Tables 7, 8, and 9 and FIGS. 5 and 6 show PK datafor example 204 in mice and cynomolgus monkey

TABLE 3 PK in fasted male Sprague Dawley Rats, IV administration.Monitor disappearance of Prodrug and appearance of riluzole.^(a)Compound of the disclosure values released riluzole values Cl AUC_(last)V_(ss) C_(max) AUC_(last) Example (L/h/Kg) t_(1/2) (h) (hr · ng/mL)(L/Kg) t_(1/2) (h) T_(max) (h) (ng/mL) (hr · ng/mL) 52 0.54 4.75 36233.55 ND 6.67 42.4 280 59 0.64 6.2 2766 5.11 ND 8 39.9 222 82 4.28 1.03663 4.14 3.07 2 198 1121 83 0.68 5.56 1725 5.06 ND 5.33 24.8 171 1110.345 6.51 4647 3.19 ND 5.33 24.6 153 113 0.69 5.45 2758 4.88 ND 6.67 92530 118 1.13 10.4 2484 3.35 16.8  0.083 49.5 165 119 1.63 9.3 1721 4.7ND 2.92 16.9 118 120 1.14 8.66 2465 3.63 76.7  0.083 30.7 132 121 2.184.83 1294 6.15 ND 1.39 49.6 286 122 3.98 0.28 219 0.861 4.01 0.08 5602017 123 3.54 0.68 787 2.04 4.13 0.14 375 1655 124 4.87 0.63 580 2.672.99 1.33 324 1577 125 1.78 1.93 1526 3.57 7.83 0.78 187 1137 125 1.671.92 1602 3.51 4.71 0.19 324 1452 173 1.34 6.7 1444 9.66 ND 8 26 159 20413.2 0.237 232 2.47 3.77 0.53 392 1300 212 6.26 2.43 218 6.21 4.64 .083315 208 216 1.38 3.98 1907 2.53 9.05 .42 156 830 234 0.853 1.5 3245 1.105.39 0.78 18.3 73.3

IV administration of prodrug at dose of 2.8 mg/Kg except example 83which was 1.8 mg/Kg and Example 212 which was dosed at 1.4 mg/Kg

ND=not determined

CL=Clearance

t_(1/2)=Terminal Half LifeVss=Volume of distributionTmax=Time at maximum concentrationCmax=Maximum concentration

TABLE 4 PK in fasted male Sprague Dawley Rats for Example 125, POadministration at 14 mg/kg. Monitor disappearance of Prodrug andappearance of riluzole. Example 125 Released Riluzole Mean SD Mean SDC_(max) (ng/mL) 213 39.0 C_(max) (ng/mL) 1587 150 t_(max) (hr) 1.80 2.00t_(max) (hr) 8.00 0 t_(1/2) (hr) 3.8 0.40 t_(1/2) (hr) ND ND AUC_(last)2259 305 AUC_(last) 20518 1437 (hr · ng/mL) (hr · ng/mL) AUC_(inf) 228932 AUC_(inf) ND ND (hr · ng/mL) (hr · ng/mL) % F 26 % F >100 % F =bioavailability

TABLE 5 PK in fasted male Sprague Dawley Rats for Example 204, POadministration at 5 mg/kg. Monitor disappearance of Prodrug andappearance of riluzole. Example 204 Riluzole Mean SD Mean SD C_(max)(ng/mL) 1.84 0.27 C_(max) (ng/mL) 442 104.0 t_(max) (hr) 0.28 0.21t_(max) (hr) 5.33 2.31 t_(1/2) (hr) ND ND t_(1/2) (hr) ND ND AUC_(last)0.90 ND AUC_(last) 2332 791 (hr · ng/mL) (hr · ng/mL)

TABLE 6 PK in fasted male Sprague Dawley Rats for Example 216, POadministration at 5 mg/kg. Monitor disappearance of Prodrug andappearance of riluzole. Example 216 Riluzole Mean SD Mean SD C_(max)(ng/mL) 2.96 0.56 C_(max) (ng/mL) 81.8 43 t_(max) (hr) 2.17 1.76 t_(max)(hr) 5.33 2.31 t_(1/2) (hr) ND ND t_(1/2) (hr) ND ND AUC_(last) 16.61.77 AUC_(last) 426 226 (hr · ng/mL) (hr · ng/mL)

TABLE 7 PK in fasted male mice for Example 204, IV administration, 1mg/kg. Monitor disappearance of Prodrug and appearance of riluzole.Example 204 Riluzole Mean SD Mean SD T_(1/2) (hr) 0.29 0.06C_(max)(ng/mL) 45 13 CL (L/hr/kg) 1.94 0.44 Tmax(hr) 083 0 Vss (L/kg)0.46 0.14 T_(1/2) (hr) 2.3 0.20 AUC_(last) 532.0 109.0 AUC_(last) 118 6(hr · ng/mL) (hr · ng/mL) AUC_(inf) 533 109.0 AUC_(inf) 130 5 (hr ·ng/mL) (hr · ng/mL)

TABLE 8 PK in fasted male mice for Example 204, PO administration, 5mg/kg. Monitor disappearance of Prodrug and appearance of riluzole.Example 204 Rilozole Mean SD Mean SD C_(max)(ng/mL) 4.71 1.52C_(max)(ng/mL) 79 26.1 Tmax(hr) 0.33 0.14 Tmax(hr) 2.0 0.0 T_(1/2) (hr)ND ND T_(1/2) (hr) ND ND AUC_(last) 3.85 2.36 AUC_(last) 332 52 (hr ·ng/mL) (hr · ng/mL) AUC_(inf) ND ND AUC_(inf) ND ND (hr · ng/mL) (hr ·ng/mL)

TABLE 9 PK in Cynomolgus Monkey for Example 204, IV administration 1mg/kg and PO administration, 3 mg/kg. Monitor the appearance ofriluzole. Riluzole from example 204 Riluzole from example 204 (IV, 1mg/kg) (PO, 3 mg/kg) Mean SD Mean SD C_(max) (ng/mL) 60 5.7 C_(max)(ng/mL) 200 89.2 t_(max) (hr) 0.75 0.3 t_(max) (hr) 2.33 0.82 t_(1/2)(hr) 6.2 1.3 t_(1/2) (hr) 5.9 2.11 AUC_(last) 293 97.9 AUC_(last) 2110920 (hr · ng/mL) (hr · ng/mL)

Inhibition of Human Melanoma Cell Xenograft Growth by Riluzole:

Melanoma C8161 cells were inoculated s.c. into nude mice at 10 per site.The mice were treated with 7.5 mg/kg riluzole (control), an equimolaramount of prodrug (Example 125, 14.6 mg/kg), and a dose of prodrugExample 125 threefold lower in molar terms (4.9 mg/kg) than the dose ofriluzole, by p.o. gavage when tumor volume had reached 6 mm³. Mice weretreated every day for 21 days, and tumor sizes were measured twiceweekly with a Vernier caliper. The results are shown in FIG. 2. Thesedata demonstrate a significant reduction in tumor volume in mice treatedwith riluzole and both doses of prodrug Example 125 compared withuntreated or vehicle-treated controls. Bars represent SD: *. P<0.01,compared with untreated and DMSO treated (t test). An additional studywas conducted using example 204 using doses of 5.0 mg/kg, 1.7 mg/kg, and0.56 mg/kg. The results of the studies using example 204 are shown inFIG. 4.

What is claimed is:
 1. A compound having formula:

including enantiomers, diasteroemers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof, wherein: R²³is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CCH,CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH₂CH₂OCH₂Ph,CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph), (CH₂)₄NH₂,(CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H,CH₂CONH₂, and CH₂CH₂CONH₂;
 2. A compound according to claim 1 selectedfrom the group consisting of:(S)-2-amino-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propanamide;(R)-2-amino-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propanamide;(S)-2-amino-3-methyl-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)butanamide;(R)-2-amino-3-methyl-N-(2-(methyl(2-oxo-2-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)butanamide;(S)-2-amino-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)-3-phenylpropanamide;(R)-2-amino-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)-3-phenylpropanamide;(S)-2-amino-4-methyl-N-(2-(methyl(2-oxo-2-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)pentanamide;(R)-2-amino-4-methyl-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)pentanamide;(S)-2-amino-3-hydroxy-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propanamide;(R)-2-amino-3-hydroxy-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propanamide;2-(2-aminoacetamido)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;or a pharmaceutically acceptable form thereof.
 3. A compositioncomprising an effective amount of at least one compound according toclaim 1 and at least one excipient.
 4. A method for treating orpreventing cancer, said method comprising administering to a subject aneffective amount of at least one compound according to claim
 1. 5. Themethod of claim 4, wherein the at least one compound is administered ina composition further comprising at least one excipient.
 6. The methodof claim 5, wherein the at least one compound is administered in acomposition further comprising an anticancer agent.
 7. The method ofclaim 6 wherein the anticancer agent is selected from the groupconsisting of Vemurafenib, Ipilimumab, Masitinib, Sorafenib,Lenalidomide, Oblimersen, Trametinib, Dabrafenib, RO5185426, Veliparib,Bosentan, YM155, CNTO 95, CR011-vcMMAE, CY503, Lenvatinib, Avastin,Tasidotin, Ramucirumab, IPI-504, Tasisulam, KW2871, MPC-6827, RAF265,Dovitinib, Everolimus, MEK162, BKM120, Nilotinib, Reolysin, 825A,Tremelimumab, PI-88, Elesclomol, STA9090, and Allovectin-7.
 8. Themethod of claim 6 wherein the cancer is selected from the groupconsisting of melanoma, nonmelanoma skin cancer, skin cancer, ovariancancer, cervical cancer, breast cancer, prostate cancer, testicularcancer, lung cancer, renal cancer, colorectal cancer, brain cancerincluding glioma and glioblastoma, and leukemia.
 9. A method fortreating or preventing a non-cancerous disease in which riluzole isclinically relevant said method comprising administering to a subject aneffective amount of at least one compound according to claim
 1. 10. Themethod of claim 9, wherein the at least one compound is administered ina composition further comprising at least one excipient.
 11. The methodof claim 9 wherein the disease in which riluzole is clinically relevantis selected from the group consisting of amyotrophic lateral sclerosis,bipolar disorder, treatment resistant and major depression, generalanxiety disorder, panic disorder, social anxiety, mood disorders,cognitive disorders, dementia, agitation, apathy, psychoses,post-traumatic stress disorders, irritability, disinhibition, learningdisorders, memory loss, personality disorders, bipolar disorders, Rettsyndrome, eating disorders, conduct disorder, neurodegenerativedisorders, pain disorders, supranuclear palsy, frontotemporal dementia,frontotemporal lobar degeneration, delirium, Alzheimer's disease, mildcognitive impairment, mild cognitive impairment due to Alzheimer'sdisease, drug addiction, tinnitus, mental retardation,obsessive-compulsive disorder, spinal muscular atrophy, radiationtherapy, multiple sclerosis, chronic cerebellar ataxia, cervicalspondylotic myelopathy, spinal cord injury, hereditary cerebellarataxia, Tourette syndrome, autism spectrum disorder, schizophrenia,fragile X syndrome, Parkinson's Disease and Huntington's disease.
 12. Amethod of attenuating presynaptic glutamate release said methodcomprising administering to a subject an effective amount of at leastone compound according to claim
 1. 13. A method of normalizing,enhancing, or potentiating the uptake of glutamate by glia, said methodcomprising administering to a subject an effective amount of at leastone compound according to claim
 1. 14. A method for treating orpreventing disease in which riluzole is clinically relevant, said methodcomprising administering to a subject an effective amount of at leastone compound according to claim 1 and a serotonin reuptake inhibitor.15. The method of claim 14 wherein the disease in which riluzole isclinically relevant is selected from the group consisting of amyotrophiclateral sclerosis, bipolar disorder, treatment resistant and majordepression, general anxiety disorder, panic disorder, social anxiety,mood disorders, cognitive disorders, dementia, agitation, apathy,psychoses, post-traumatic stress disorders, irritability, disinhibition,learning disorders, memory loss, personality disorders, bipolardisorders, Rett syndrome, eating disorders, conduct disorder,neurodegenerative disorders, pain disorders, supranuclear palsy,frontotemporal dementia, frontotemporal lobar degeneration, delirium,Alzheimer's disease, mild cognitive impairment, mild cognitiveimpairment due to Alzheimer's disease, drug addiction, tinnitus, mentalretardation, obsessive-compulsive disorder, spinal muscular atrophy,radiation therapy, multiple sclerosis, chronic cerebellar ataxia,hereditary spinocerebellar ataxia, spinocerebellar ataxia, sporadicataxia, episodic ataxia, Friedreich Ataxia, Multisystem Atrophy, ataxiaassociated with Anti-GAD antibodies target and onconeural antigen,essential tremor, cervical spondylotic myelopathy, spinal cord injury,hereditary cerebellar ataxia, Tourette syndrome, autism spectrumdisorder, schizophrenia, fragile X syndrome, Parkinson's Disease,Progressive Supranuclear Palsy, Dementia with Lewy Bodies andHuntington's disease.